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1

Turn structures in CGRP C-terminal analogues promote stable arrangements of key residue side chains.  

PubMed

The 37-amino acid calcitonin gene-related peptide (CGRP) is a potent endogenous vasodilator thought to be implicated in the genesis of migraine attack. CGRP antagonists may thus have therapeutic value for the treatment of migraine. The CGRP C-terminally derived peptide [D(31),P(34),F(35)]CGRP(27-37)-NH(2) was recently identified as a high-affinity hCGRP(1) receptor selective antagonist. Reasonable CGRP(1) affinity has also been demonstrated for several related analogues, including [D(31),A(34),F(35)]CGRP(27-37)-NH(2). In the study presented here, conformational and structural features in CGRP(27-37)-NH(2) analogues that are important for hCGRP(1) receptor binding were explored. Structure-activity studies carried out on [D(31),P(34),F(35)]CGRP(27-37)-NH(2) resulted in [D(31),P(34),F(35)]CGRP(30-37)-NH(2), the shortest reported CGRP C-terminal peptide analogue exhibiting reasonable hCGRP(1) receptor affinity (K(i) = 29.6 nM). Further removal of T(30) from the peptide's N-terminus greatly reduced receptor affinity from the nanomolar to micromolar range. Additional residues deemed critical for hCGRP(1) receptor binding were identified from an alanine scan of [A(34),F(35)]CGRP(28-37)-NH(2) and included V(32) and F(37). Replacement of the C-terminal amide in this same peptide with a carboxyl, furthermore, resulted in a greater than 50-fold reduction in hCGRP(1) affinity, thus suggesting a direct role for the amide moiety in receptor binding. The conformational properties of two classes of CGRP(27-37)-NH(2) peptides, [D(31),X(34),F(35)]CGRP(27-37)-NH(2) (X is A or P), were examined by NMR spectroscopy and molecular modeling. A beta-turn centered on P(29) was a notable feature consistently observed among active peptides in both series. This turn led to exposure of the critical T(30) residue to the surrounding environment. Peptides in the A(34) series were additionally characterized by a stable C-terminal helical turn that resulted in the three important residues (T(30), V(32), and F(37)) adopting consistent interspatial positions with respect to one another. Peptides in the P(34) series were comparatively more flexible at the C-terminus, although a large proportion of the [D(31),P(34),F(35)]CGRP(27-37)-NH(2) calculated conformers contained a gamma-turn centered on P(34). These results collectively suggest that turn structures at both the C-terminus and N-terminus of CGRP(27-37)-NH(2) analogues may help to appropriately orient critical residues (T(30), V(32), and F(37)) for hCGRP(1) receptor binding. PMID:11444978

Carpenter, K A; Schmidt, R; von Mentzer, B; Haglund, U; Roberts, E; Walpole, C

2001-07-27

2

Use of pyrethroid analogues to identify key structural features for enhanced esterase resistance in Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae).  

PubMed

It has been reported previously that the major resistance mechanism to pyrethroid insecticides by the cotton bollworm Helicoverpa armigera (Hübner) in Australia is a consequence of overproduction of esterase isoenzymes. This paper reports structure-activity relationships that support such a view, based on in vivo bioassays conducted with a range of pyrethroid structures containing a variety of acid and alcohol moieties and the correlation with in vitro esterase inhibition assays against the same structures, and identifies the critical regions of the molecule with regard to esterase inhibition, and hence resistance. The implications of this work in terms of possible resistance management are evaluated and discussed. PMID:17469082

Gunning, Robin V; Moores, Graham D; Jewess, Philip; Boyes, Alastair L; Devonshire, Alan L; Khambay, Bhupinder P S

2007-06-01

3

Total Synthesis of Vinblastine, Related Natural Products, and Key Analogues and Development of Inspired Methodology Suitable for the Systematic Study of Their Structure–Function Properties  

PubMed Central

Conspectus Biologically active natural products composed of fascinatingly complex structures are often regarded as not amenable to traditional systematic structure–function studies enlisted in medicinal chemistry for the optimization of their properties beyond what might be accomplished by semisynthetic modification. Herein, we summarize our recent studies on the Vinca alkaloids vinblastine and vincristine, often considered as prototypical members of such natural products, that not only inspired the development of powerful new synthetic methodology designed to expedite their total synthesis but have subsequently led to the discovery of several distinct classes of new, more potent, and previously inaccessible analogues. With use of the newly developed methodology and in addition to ongoing efforts to systematically define the importance of each embedded structural feature of vinblastine, two classes of analogues already have been discovered that enhance the potency of the natural products >10-fold. In one instance, remarkable progress has also been made on the refractory problem of reducing Pgp transport responsible for clinical resistance with a series of derivatives made accessible only using the newly developed synthetic methodology. Unlike the removal of vinblastine structural features or substituents, which typically has a detrimental impact, the additions of new structural features have been found that can enhance target tubulin binding affinity and functional activity while simultaneously disrupting Pgp binding, transport, and functional resistance. Already analogues are in hand that are deserving of full preclinical development, and it is a tribute to the advances in organic synthesis that they are readily accessible even on a natural product of a complexity once thought refractory to such an approach. PMID:25586069

2015-01-01

4

Total synthesis of vinblastine, related natural products, and key analogues and development of inspired methodology suitable for the systematic study of their structure-function properties.  

PubMed

Biologically active natural products composed of fascinatingly complex structures are often regarded as not amenable to traditional systematic structure-function studies enlisted in medicinal chemistry for the optimization of their properties beyond what might be accomplished by semisynthetic modification. Herein, we summarize our recent studies on the Vinca alkaloids vinblastine and vincristine, often considered as prototypical members of such natural products, that not only inspired the development of powerful new synthetic methodology designed to expedite their total synthesis but have subsequently led to the discovery of several distinct classes of new, more potent, and previously inaccessible analogues. With use of the newly developed methodology and in addition to ongoing efforts to systematically define the importance of each embedded structural feature of vinblastine, two classes of analogues already have been discovered that enhance the potency of the natural products >10-fold. In one instance, remarkable progress has also been made on the refractory problem of reducing Pgp transport responsible for clinical resistance with a series of derivatives made accessible only using the newly developed synthetic methodology. Unlike the removal of vinblastine structural features or substituents, which typically has a detrimental impact, the additions of new structural features have been found that can enhance target tubulin binding affinity and functional activity while simultaneously disrupting Pgp binding, transport, and functional resistance. Already analogues are in hand that are deserving of full preclinical development, and it is a tribute to the advances in organic synthesis that they are readily accessible even on a natural product of a complexity once thought refractory to such an approach. PMID:25586069

Sears, Justin E; Boger, Dale L

2015-03-17

5

The International Space Analogue Rock Store (ISAR): A key tool for future planetary exploration.  

NASA Astrophysics Data System (ADS)

In order to prepare the next in situ space missions we have created a « lithothèque » of analogue rocks for calibrating and testing future (and existing) space flight instruments. This rock collection is called the International Space Analogue Rockstore (ISAR) and is hosted in the CNRS and the Observatoire des Sciences de l'Univers en Region Centre (OSUC) in Orléans. For maximum science return, all instruments on a single mission should ideally be tested with the same suite of relevant analogue materials. The ISAR lithothéque aims to fulfill this role by providing suitable materials to instrument teams [1]. The lithothèque is accompanied by an online database of all relevant structural, textural, and geochemical data (www.isar.cnrs-orleans.fr).The data base will also be available during missions to aid interpretation of data obtained in situ. Mars is the immediate goal for MSL-2011 and the new international Mars 2018 mission. The lithothèque thus presently contains relevant Mars-analogue rock and mineral samples, a preliminary range of which is now available to the scientific community for instrument testing [2]. The preliminary group of samples covers a range of lithologies to be found on Mars, especially those in Noachain/Hesperian terrains where MSL will land (Gale Crater) and where the 2018 landing site will most likely be located. It includes a variety of basalts (tephrite, primitive basalt, silicified basalt; plus cumulates), komatiites, artificially synthesized martian basalts [3], volcanic sands, a banded iron formation, carbonates associated with volcanic lithologies and hydrothermalism, the clay Nontronite, and hydrothermal cherts. Some of the silicified volcanic sands contain traces of early life that are good analogues for potential martian life [4]. [1] Westall F. et al., LPI contribution 1608, 1346, 42nd LPSC, 2011; [2] Bost N. et al., in review (Icarus); [3] Bost N. et al., in review (Meteoritics); [4] Westall et al., 2011, Planetary and Space Science 59. ISAR Team: N. Bost, F. Westall, C; Ramboz, F. Foucher, D. Pullan, T. Zegers, B. Hoffman, F. Rull, J. Bridges, A; Steele, H. Amundsen, R. Barbieri, A. Hubert, B. Cavalazzi, J. Bridges, M. Viso, J. Vago, S. Petit, A. Meunier, I. Fleischer, G. Klingelhöfer, N. Arndt…

Bost, N.; Westall, F.; Ramboz, C.; Foucher, F.

2012-04-01

6

Separation of structurally similar nocathiacin analogues by reversed phase chromatography.  

PubMed

The complete separation of structurally similar compounds has been a challenge due mainly to their similarity on physical and chemical properties. In the present study, a simple and effective chromatographic method to separate and purify nocathiacin acid from its structural analogue nocathiacin I was developed. After evaluating mobile phase compositions on the retention characteristics by reversed phase high-performance liquid chromatography (HPLC), the elution order of nocathiacin I and nocathiacin acid was completely reversed, and the resolution value between the two analogues was improved, by varying pH value and ionic strength, to greater than 10 from merged peaks under initial conditions. In addition, a preparative isolation of nocathiacin acid was performed by reversed phase column chromatography under the guidance of the HPLC study. This chromatographic method resulted in an efficient process to obtain pure nocathiacin acid with a recovery rate of 83%. The present approach offers a new methodology for the separation of structurally closely related secondary metabolites. PMID:20303091

Wei, Maochen; Wang, Suzhen; He, Yunmian; Fang, Yongliang; Chen, Yijun

2010-04-30

7

The crystal structure of faustite and its copper analogue turquoise  

Microsoft Academic Search

The crystal structure of faustite, ZnAI6(P04MOHhAH20, was determined using single-crystal data (Mo-KIX X-radiation, CCD area detector, 1624 unique reflections, RI = 4.91 %, wR2 = 9.23%), and compared with results of a reinvestigation of the structure of its copper analogue turquoise, CuAI6(P04MOH)gAH20 (2737 unique reflections, RI = 2.81%, wR2 = 6.90%). Both are isostructural and crystallize in space group PI,

U. Kolitsch; G. Giester

2000-01-01

8

Structural and Vibrational Properties of Boron Nitride Analogues of Diamondoids  

NASA Astrophysics Data System (ADS)

Diamondoids are stable cage-like hydrocabon molecules that possess a structure that is superimposable upon the diamond crystal. These highly symmetric structures have a generic structural formula C4n+6H4n+12, and they have been isolated from petroleum oil. Because of their various shapes and sizes, there has been speculation in the literature that diamondoids might be suitable building blocks for possible applications in nanotechnology. One could ask whether boron nitride (BN) analogues of diamondoids might exist. It is known experimentally that cyclotriborazane (B3N3H12), the BN-analogue of the smallest diamondoid molecule adamantane exists, but there is no experimental evidence for the existence of higher-order BN-diamondoids at the present time. In this work we perform accurate all-electron density-functional theory (DFT) calculations to study the structural and vibrational properties of a small set of lower order BN-diamondoids (e.g. BN-adamantane (B6N4H16), BN-diamantane (B7N7H20), BN-triamantane (B10N8H24), and BN-anti-tetramantane (B11N11H24)). We discuss the relative stability of each of these representative BN-diamondoid molecules and provide theoretical infrared and Raman spectra for future identification of this novel class of molecules.*This work was supported by the National Science Foundation and the Office of Naval Research.

Richardson, Steven L.; Park, Kyungwha; Baruah, Tunna; Pederson, Mark R.

2006-03-01

9

Functional and structural characteristics of anticancer peptide Pep27 analogues  

PubMed Central

Background A secreted peptide Pep27 initiates the cell death program in S. pneumoniae through signal transduction. This study was undertaken to evaluate the relation between the structure and cytotoxic activity of Pep27 and its analogues on cancer cells. Results Pep27anal2 characterized substituting (2R?W), (4E?W), (11S?W) and (13Q?W) in native Pep27, exhibited greater hydrophobicity and anticancer activity than Pep27 and other analogues. The IC50 values of Pep27anal2 were approximately 10 – 30 ?M in a number of cell lines (AML-2, HL-60, Jurkat, MCF-7 and SNU-601). Confocal microscopy showed that Pep27anal2-FITC was localized in the plasma membrane, and then moving from the membrane to subcellular compartments with the initiation of membrane blebbing. Flow cytometric analysis using propidium iodide and Annexin V also revealed that Pep27anal2 induced apoptosis with minor membrane damage. Electron microscopy revealed that Pep27 induced apoptosis in Jurkat cells. The anticancer activity of Pep27anal2 was neither abrogated by pan-caspase inhibitor (Z-VAD-fmk) nor related to cytochrome c release from mitochondria. The 3D solution structures of these two Pep27 peptides revealed that both form a random coil conformation in water; however, they adopted stable ?-helical conformations in solutions. Conclusion The results indicate that Pep27anal2 can penetrate the plasma membrane, and then induce apoptosis in both caspase-and cytochrome c-independent manner. The hydrophobicity of Pep27anal2 appears to play an important role in membrane permeabilization and/or anticancer properties. The structure-functional relationships of these peptides are also discussed. It is proposed that Pep27anal2 is a potential candidate for anticancer therapeutic agents. PMID:16004618

Lee, Dong Gun; Hahm, Kyung-Soo; Park, Yoonkyung; Kim, Hai-Young; Lee, Weontae; Lim, Sung-Chul; Seo, Youn-Kyung; Choi, Cheol-Hee

2005-01-01

10

Preparing to return to the Moon: Lessons from science-driven analogue missions to the Mistastin Lake impact structure, Canada, a unique lunar analogue site  

NASA Astrophysics Data System (ADS)

Impact cratering is the dominant geological process on the Moon, Near Earth Asteroids (NEAs) and the moons of Mars - the objectives for the new Solar System Exploration Research Virtual Institute (SSERVI). Led by members of the Canadian Lunar Research Network (CLRN), funded by the Canadian Space Agency, and with participants from the U.S., we carried out a series of analogue missions on Earth in order to prepare and train for future potential robotic and human sample return missions. Critically, these analogue missions were driven by the paradigm that operational and technical objectives are conducted while conducting new science and addressing real overarching scientific objectives. An overarching operational goal was to assess the utility of a robotic field reconnaissance mission as a precursor to a human sortie sample return mission. Here, we focus on the results and lessons learned from a robotic precursor mission and follow on human-robotic mission to the Mistastin Lake impact structure in Labrador, northern Canada (55°53'N; 63°18'W). The Mistastin structure was chosen because it represents an exceptional analogue for lunar craters. This site includes both an anorthositic target, a central uplift, well-preserved impact melt rocks - mostly derived from melting anorthosite - and is (or was) relatively unexplored. This crater formed ~36 million years ago and has a diameter of ~28 km. The scientific goals for these analogue missions were to further our understanding of impact chronology, shock processes, impact ejecta and potential resources within impact craters. By combining these goals in an analogue mission campaign key scientific requirements for a robotic precursor were determined. From the outset, these analogue missions were formulated and executed like an actual space mission. Sites of interest were chosen using remote sensing imagery without a priori knowledge of the site through a rigorous site selection process. The first deployment occurred in August and September 2010 and involved simulated robotic surveying of selected 'landing sites' at the Mistastin structure. The second deployment took place at the same location in 2011, which included simulated astronaut surface operations with, and without, the aid of a robotic assistant. A mission control team, based at the University of Western Ontario, London, Ontario, 1,900 km from the field site, oversaw operations. Our study showed the value of precursor reconnaissance missions in providing surface geology visualization at resolutions and from viewpoints not achievable from orbit, including high-resolution surface imagery on the scale of 10s of metres to kilometres. Indeed, data collected during the robotic precursor mission led to the formulation of a hypothesis that a large impact melt outcrop - named Discovery Hill - represents an impact melt pond in the terraced region of the crater, analogous to similar ponds of melt documented around the rim of well-preserved lunar craters such as Tycho. Further discoveries, that will be highlight here, include documentation of ejecta deposits for the first time at Mistastin, quantification of shock in anorthosites, and refined age estimates for the Mistastin impact event.

Osinski, G. R.; Barfoot, T.; Chanou, A.; Daly, M. G.; Francis, R.; Hodges, K. V.; Jolliff, B. L.; Mader, M. M.; McCullough, E. M.; Moores, J. E.; Pickersgill, A.; Pontefract, A.; Preston, L.; Shankar, B.; Singleton, A.; Sylvester, P.; Tornabene, L. L.; Young, K. E.

2013-12-01

11

The Manicouagan impact structure as a terrestrial analogue site for lunar and martian planetary science  

Microsoft Academic Search

The 90 km diameter, late Triassic Manicouagan impact structure of Québec, Canada, is a well-preserved, undeformed complex crater possessing an anorthositic central uplift and a 55 km diameter melt sheet. As such, it provides a valuable terrestrial analogue for impact structures developed on other planetary bodies, especially the Moon and Mars, which are currently the focus of exploration initiatives. The

John G. Spray; Lucy M. Thompson; Marc B. Biren; Catherine O'Connell-Cooper

2010-01-01

12

The Manicouagan impact structure as a terrestrial analogue site for lunar and martian planetary science  

Microsoft Academic Search

The 90km diameter, late Triassic Manicouagan impact structure of Québec, Canada, is a well-preserved, undeformed complex crater possessing an anorthositic central uplift and a 55km diameter melt sheet. As such, it provides a valuable terrestrial analogue for impact structures developed on other planetary bodies, especially the Moon and Mars, which are currently the focus of exploration initiatives. The scientific value

John G. Spray; Lucy M. Thompson; Marc B. Biren; Catherine O’Connell-Cooper

2010-01-01

13

Dicarba analogues of ?-conotoxin RgIA. Structure, stability, and activity at potential pain targets.  

PubMed

?-Conotoxin RgIA is both an antagonist of the ?9?10 nicotinic acetylcholine receptor (nAChR) subtype and an inhibitor of high-voltage-activated N-type calcium channel currents. RgIA has therapeutic potential for the treatment of pain, but reduction of the disulfide bond framework under physiological conditions represents a potential liability for clinical applications. We synthesized four RgIA analogues that replaced native disulfide pairs with nonreducible dicarba bridges. Solution structures were determined by NMR, activity assessed against biological targets, and stability evaluated in human serum. [3,12]-Dicarba analogues retained inhibition of ACh-evoked currents at ?9?10 nAChRs but not N-type calcium channel currents, whereas [2,8]-dicarba analogues displayed the opposite pattern of selectivity. The [2,8]-dicarba RgIA analogues were effective in HEK293 cells stably expressing human Cav2.2 channels and transfected with human GABAB receptors. The analogues also exhibited improved serum stability over the native peptide. These selectively acting dicarba analogues may represent mechanistic probes to explore analgesia-related biological receptors. PMID:25393758

Chhabra, Sandeep; Belgi, Alessia; Bartels, Peter; van Lierop, Bianca J; Robinson, Samuel D; Kompella, Shiva N; Hung, Andrew; Callaghan, Brid P; Adams, David J; Robinson, Andrea J; Norton, Raymond S

2014-12-11

14

Structure-activity relationships of unsaturated analogues of valproic acid.  

PubMed

The principal metabolite of valproic acid (VPA), 2-ene VPA, appears to share most of VPA's pharmacological and therapeutic properties while lacking its hepatotoxicity and teratogenicity, thus making it a useful lead compound for the development of safer antiepileptic drugs. Analogues of 2-ene VPA were evaluated for anticonvulsant activity in mice using the subcutaneous pentylenetetrazole test. Cyclooctylideneacetic acid exhibited a potency markedly exceeding that of VPA itself with only modest levels of sedation. Potency, as either ED50 or brain concentration, was highly correlated (r > 0.85) with volume and lipophilicity rather than with one of the shape parameters calculated by molecular modeling techniques, arguing against the existence of a specific receptor site. Instead, a role for the plasma membrane in mediating the anticonvulsant effect is suggested. PMID:7650693

Palaty, J; Abbott, F S

1995-08-18

15

Synthesis and Structure activity relationships of EGCG Analogues, A Recently Identified Hsp90 Inhibitor  

PubMed Central

Epigallocatechin-3-gallate (EGCG), the principal polyphenol isolated from green tea, was recently shown to inhibit Hsp90, however structure-activity relationships for this natural product have not yet been produced. Herein, we report the synthesis and biological evaluation of EGCG analogues to establish structure-activity relationships between EGCG and Hsp90. All four rings as well as the linker connecting the C- and the D-rings were systematically investigated, which led to the discovery of compounds that inhibit Hs90 and display improvement in efficacy over EGCG. Anti-proliferative activity of all the analogues was determined against MCF-7 and SKBr3 cell lines and Hsp90 inhibitory activity of four most potent analogues was further evaluated by western blot analyses and degradation of Hsp90-dependent client proteins. Prenyl substituted aryl ester of 3,5-dihydroxychroman-3-ol ring system was identified as novel scaffold that exhibit Hsp90 inhibitory activity. PMID:23834230

Khandelwal, Anuj; Hall, Jessica

2014-01-01

16

Key structural features of cis-cinnamic acid as an allelochemical.  

PubMed

1-O-cis-cinnamoyl-?-D-glucopyranose is one of the most potent allelochemicals isolated from Spiraea thunbergii Sieb. It is suggested that it derives its strong inhibitory activity from cis-cinnamic acid, which is crucial for phytotoxicity. It was synthesized to confirm its structure and bioactivity, and also a series of cis-cinnamic acid analogues were prepared to elucidate the key features of cis-cinnamic acid for lettuce root growth inhibition. The cis-cyclopropyl analogue showed potent inhibitory activity while the saturated and alkyne analogues proved to be inactive, demonstrating the importance of the cis-double bond. Moreover, the aromatic ring could not be replaced with a saturated ring. However, the 1,3-dienylcyclohexene analogue showed strong activity. These results suggest that the geometry of the C-C double bond between the carboxyl group and the aromatic ring is essential for potent inhibitory activity. In addition, using several light sources, the photostability of the cinnamic acid derivatives and the role of the C-C double bond were also investigated. PMID:22959226

Abe, Masato; Nishikawa, Keisuke; Fukuda, Hiroshi; Nakanishi, Kazunari; Tazawa, Yuta; Taniguchi, Tomoya; Park, So-Young; Hiradate, Syuntaro; Fujii, Yoshiharu; Okuda, Katsuhiro; Shindo, Mitsuru

2012-12-01

17

Novel biological effects of alloferon and its selected analogues: structure-activity study.  

PubMed

The subject of this paper is a search for new biological properties of alloferon (H-His-Gly-Val-Ser-Gly-His-Gly-Gln-His-Gly-Val-His-Gly-OH) and a series of its analogues. The studies on structure/activity relationship in alloferon, the synthesis of a series of 28 analogues were performed. The analogues were modified at position 1 or 6, and other were oligopeptides with a shortened peptide sequence. Biological effects of the peptides were evaluated by the pro-apoptotic action in vivo on haemocytes of Tenebrio molitor and in the cardiotropic test in vitro on the heart of T. molitor and Zophobas atratus. In the in vivo bioassays, new biological activities of alloferon and its analogues were discovered. In haemocytotoxic bioassay, alloferon strongly induces T. molitor haemocytes to undergo apoptosis at a dose of 10 nM. Moreover, [Phe(p-NH2)(1)]-, [Tyr(6)]- and [1-10]-alloferon exhibit a two-fold increase of caspases activation in comparison with the alloferon. However, alloferon and its analogues show a weak cardiostimulatory activity in Z. atratus but the heart of T. molitor is not sensitive to these peptides. The results obtained here suggest that alloferon plays pleiotropic functions in insects. PMID:23499798

Kuczer, Mariola; Czarniewska, El?bieta; Rosi?ski, Grzegorz

2013-05-10

18

New Structures and Bioactivity Properties of Jasplakinolide (Jaspamide) Analogues from Marine Sponges  

PubMed Central

The goal of this study was to isolate and study additional jasplakinolide analogues from two taxonomically distinct marine sponges including two Auletta spp. and one Jaspis splendens. This led to the isolation of jasplakinolide (1) and eleven jasplakinolide analogues (3 – 13) including seven new analogues (6 – 10, 12, and 13). Structure elucidation of the new compounds was based on a combination of 1D and 2D NMR analysis, optical rotation, circular dichroism, and preparation of Mosher’s esters. Five of the new compounds are oxidized tryptophan derivatives of 1, including a unique quinazoline derivative (9). Compounds 1, 3, 5 – 8, and 11 were evaluated in the NCI 60 cell line screen and all compounds were tested in a microfilament disruption assay. Jasplakinolide B (11) exhibited potent cytotoxicity (GI50 < 1 nM vs. human colorectal adenocarcinoma (HCT-116) cells) but did not exhibit microfilament-disrupting activity at 80 nM. PMID:20121114

Robinson, Sarah J.; Morinaka, Brandon I.; Amagata, Taro; Tenney, Karen; Bray, Walter M.; Gassner, Nadine C.; Lokey, R. Scott; Crews, Phillip

2010-01-01

19

Characterization and use of an unprecedentedly bright and structurally non-perturbing fluorescent DNA base analogue  

Microsoft Academic Search

This article presents the first evidence that the DNA base analogue 1,3-diaza-2-oxophenoxazine, tCO, is highly fluorescent, both as free nucleoside and incorporated in an arbitrary DNA structure. tCO is thoroughly characterized with respect to its photo- physical properties and structural performance in single- and double-stranded oligonucleotides. The lowest energy absorption band at 360 nm (e ¼ 9000 M21 cm21) is

Peter Sandin; Karl Borjesson; Hong Li; Jerker Ma; Tom Brown; L. Marcus Wilhelmsson; Bo Albinsson

2008-01-01

20

Structural colour: Opal analogue discovered in a weevil  

NASA Astrophysics Data System (ADS)

Beetles in dimly lit tropical forests often display structural colours, but in direct sunlight only part of the insect can be seen from any direction - it appears as a spot of light because multilayer reflectors on its rounded surface act like mirrors. Here we describe a beetle, Pachyrhynchus argus, found in forests in northeastern Queensland, Australia, that has a metallic coloration that is visible from any direction owing to a photonic crystal structure analogous to that of opal. To our knowledge, this is the first recorded example of an opal-type structure in an animal.

Parker, Andrew R.; Welch, Victoria L.; Driver, Dominique; Martini, Natalia

2003-12-01

21

Structure-activity relationship analysis of curcumin analogues on anti-influenza virus activity.  

PubMed

Curcumin (Cur) is a commonly used colouring agent and spice in food. Previously, we reported that Cur inhibits type A influenza virus (IAV) infection by interfering with viral haemagglutination (HA) activity. To search for a stable Cur analogue with potent anti-IAV activity and to investigate the structure contributing to its anti-IAV activity, a comparative analysis of structural and functional analogues of Cur, such as tetrahydrocurcumin (THC) and petasiphenol (Pet), was performed. The result of time-of-drug addition tests indicated that these curcuminoids were able to inhibit IAV production in cell cultures. Noticeably, Pet and THC inhibit IAV to a lesser extent than Cur, which is in line with their effect on reducing plaque formation when IAV was treated with Cur analogues before infection. Unexpectedly, both THC and Pet did not harbour any HA inhibitory effect. It should be noted that the structure of Pet and THC differs from Cur with respect to the number of double bonds present in the central seven-carbon chain, and structure modelling of Cur analogues indicates that the conformations of THC and Pet are distinct from that of Cur. Moreover, simulation docking of Cur with the HA structure revealed that Cur binds to the region constituting sialic acid anchoring residues, supporting the results obtained by the inhibition of HA activity assay. Collectively, structure-activity relationship analyses indicate that the presence of the double bonds in the central seven-carbon chain enhanced the Cur -dependent anti-IAV activity and also that Cur might interfere with IAV entry by its interaction with the receptor binding region of viral HA protein. PMID:24034558

Ou, Jun-Lin; Mizushina, Yoshiyuki; Wang, Sheng-Yang; Chuang, Duen-Yau; Nadar, Muthukumar; Hsu, Wei-Li

2013-11-01

22

The development of structures in analogue and natural debris avalanches  

NASA Astrophysics Data System (ADS)

All types of rockslide-debris avalanches present a plethora of internal structures that are also well observed on the surface. Many of these are seen as faults and folds that can be used to determine deformation history and kinematics. We present two sets of simple and well-constrained experiments of reduced basal friction laboratory rockslides, equivalent to a highly deformed simple shear layer, with plug-flow. These follow the original ramp-slide work of Shea and van Wyk de Vries (Geosphere, 2008). The experiments used a curved ramp where materials accelerate until reaching a gently-sloped depositional surface and a constantly inclined ramp with a more regular slope and longer slides. A detailed description of deposit structures, their sequential formation and morphology is then used to investigate the transport type and deformation chronology from slide initiation to runout stopping of avalanches. Results using a curved ramp show accumulation and thickening at where the slope decreases. The thickened mass then further remobilises and advances by secondary collapse of the mass. Such a stop-start process may be important in many mountainous avalanches where there are rapid changes in slope. The constantly inclined ramp shows shearing and extensional structures at the levees and a set of compression and extension structures in the middle. We noted that frontal accumulation during flow occurs as materials at the front move slower relative to those in the medial and proximal zones. This also leads to secondary frontal collapse, and helps to maintain a thicker mass that can flow further. Descriptions and analyses of these structures are then applied to the kinematics and dynamics of natural examples. We study the 2006 Guinsaugon Rockslide event in the Philippines and find that frontal accumulation and secondary avalanching had also occurred and were important in determining the distribution and runout of the mass. Frontal bulking and collapse may also have occurred at the Tacna Avalanche, Peru and the Pajonales-Aracar event in Argentina.

Paguican, Engielle Mae; van Wyk de Vries, Benjamin; Mahar Francisco Lagmay, Alfredo; Grosse, Pablo

2010-05-01

23

Characterization and use of an unprecedentedly bright and structurally non-perturbing fluorescent DNA base analogue  

PubMed Central

This article presents the first evidence that the DNA base analogue 1,3-diaza-2-oxophenoxazine, tCO, is highly fluorescent, both as free nucleoside and incorporated in an arbitrary DNA structure. tCO is thoroughly characterized with respect to its photophysical properties and structural performance in single- and double-stranded oligonucleotides. The lowest energy absorption band at 360 nm (? = 9000 M?1 cm?1) is dominated by a single in-plane polarized electronic transition and the fluorescence, centred at 465 nm, has a quantum yield of 0.3. When incorporated into double-stranded DNA, tCO shows only minor variations in fluorescence intensity and lifetime with neighbouring bases, and the average quantum yield is 0.22. These features make tCO, on average, the brightest DNA-incorporated base analogue so far reported. Furthermore, it base pairs exclusively with guanine and causes minimal perturbations to the native structure of DNA. These properties make tCO a promising base analogue that is perfectly suited for e.g. photophysical studies of DNA interacting with macromolecules (proteins) or for determining size and shape of DNA tertiary structures using techniques such as fluorescence anisotropy and fluorescence resonance energy transfer (FRET). PMID:18003656

Sandin, Peter; Börjesson, Karl; Li, Hong; Mårtensson, Jerker; Brown, Tom; Wilhelmsson, L. Marcus; Albinsson, Bo

2008-01-01

24

Synthesis, cytotoxic activity and structure-activity relationships of hedychenone analogues.  

PubMed

Hedychenone, a plant-derived labdane diterpenoid, showed potent in vitro cytotoxic activity against cancerous cells. In the present study, a series of analogues have been synthesized by modification of the furanoid ring, double bond and the vinylic methyl functionality of this natural product lead and evaluated for their cytotoxic activities against human cancer cell lines. The structures of the target compounds were established by IR, (1)H NMR and mass spectral analysis. Majority of the analogues displayed potent activity than the parent compound, hedychenone. Preliminary structure-activity relationship studies indicated that furanoid ring has a greater impact on cytotoxicity than that of the decalone nucleus. However, dimerization through C-8 significantly enhanced the cytotoxic activity of the hedychenone. PMID:20303755

Prabhakar Reddy, P; Lavekar, Aditya G; Suresh Babu, K; Ranga Rao, R; Shashidhar, J; Shashikiran, G; Madhusudana Rao, J

2010-04-15

25

Antioxidant, prooxidant and cytotoxic activity of hydroxylated resveratrol analogues: structure–activity relationship  

Microsoft Academic Search

Resveratrol (trans-3,4?,5-trihydroxystilbene), a naturally occurring hydroxystilbene, is considered an essential antioxidative constituent of red wine possessing chemopreventive properties. However, resveratrol and even more its metabolite piceatannol were reported to have also cytostatic activities. In order to find out whether this is related to antioxidative properties of those compounds, we synthesized five other polyhydroxylated resveratrol analogues and studied structure–activity relationships between

Marek Murias; Walter Jäger; Norbert Handler; Thomas Erker; Zsuzsanna Horvath; Thomas Szekeres; Hans Nohl; Lars Gille

2005-01-01

26

Structure of Mandelate Racemase with Bound Intermediate Analogues Benzohydroxamate and Cupferron†  

PubMed Central

Mandelate racemase (MR, EC 5.1.2.2) from Pseudomonas putida catalyzes the Mg2+-dependent interconversion of the enantiomers of mandelate, stabilizing the altered substrate in the transition state by 26 kcal/mol relative to the substrate in the ground state. To understand the origins of this binding discrimination, we solved the X-ray crystal structures of wild-type MR complexed with two analogues of the putative aci-carboxylate intermediate, benzohydroxamate and cupferron, to 2.2-Å resolution. Benzohydroxamate is shown to be a reasonable mimic of the transition state/intermediate since its binding affinity to 21 MR variants correlates well with changes in the free energy of transition state stabilization afforded by these variants. Both benzohydroxamate and cupferron chelate the active site divalent metal ion and are bound in a conformation with the phenyl ring coplanar with the hydroxamate and diazeniumdiolate moieties, respectively. Structural overlays of MR complexed with benzohydroxamate, cupferron, and the ground state analogue (S)-atrolacatate reveal that the para-carbon of the substrate phenyl ring moves by 0.8–1.2 Å between the ground state and intermediate state, consistent with the proposal that the phenyl ring moves during MR catalysis while the polar groups remain relatively fixed. Although the overall protein structure of MR with bound intermediate analogues is very similar to MR with bound (S)-atrolactate, the intermediate-Mg2+ distance shortens, suggesting a tighter complex with the catalytic Mg2+. In addition, Tyr 54 moves nearer to the phenyl ring of the bound intermediate analogues, contributing to an overall constriction of the active site cavity. However, site-directed mutagenesis experiments revealed that the role of Tyr 54 in MR catalysis is relatively minor, suggesting that alterations in enzyme structure that contribute to discrimination between the altered substrate in the transition state and the ground state by this proficient enzyme are extremely subtle. PMID:22264153

Lietzan, Adam D.; Nagar, Mitesh; Pellmann, Elise A.; Bourque, Jennifer R.; Bearne, Stephen L.; St Maurice, Martin

2012-01-01

27

Structure of Mandelate Racemase with Bound Intermediate Analogues Benzohydroxamate and Cupferron  

SciTech Connect

Mandelate racemase (MR, EC 5.1.2.2) from Pseudomonas putida catalyzes the Mg{sup 2+}-dependent interconversion of the enantiomers of mandelate, stabilizing the altered substrate in the transition state by 26 kcal/mol relative to the substrate in the ground state. To understand the origins of this binding discrimination, we determined the X-ray crystal structures of wild-type MR complexed with two analogues of the putative aci-carboxylate intermediate, benzohydroxamate and Cupferron, to 2.2-{angstrom} resolution. Benzohydroxamate is shown to be a reasonable mimic of the transition state and/or intermediate because its binding affinity for 21 MR variants correlates well with changes in the free energy of transition state stabilization afforded by these variants. Both benzohydroxamate and Cupferron chelate the active site divalent metal ion and are bound in a conformation with the phenyl ring coplanar with the hydroxamate and diazeniumdiolate moieties, respectively. Structural overlays of MR complexed with benzohydroxamate, Cupferron, and the ground state analogue (S)-atrolactate reveal that the para carbon of the substrate phenyl ring moves by 0.8-1.2 {angstrom} between the ground state and intermediate state, consistent with the proposal that the phenyl ring moves during MR catalysis while the polar groups remain relatively fixed. Although the overall protein structure of MR with bound intermediate analogues is very similar to that of MR with bound (S)-atrolactate, the intermediate-Mg{sup 2+} distance becomes shorter, suggesting a tighter complex with the catalytic Mg{sup 2+}. In addition, Tyr 54 moves closer to the phenyl ring of the bound intermediate analogues, contributing to an overall constriction of the active site cavity. However, site-directed mutagenesis experiments revealed that the role of Tyr 54 in MR catalysis is relatively minor, suggesting that alterations in enzyme structure that contribute to discrimination between the altered substrate in the transition state and the ground state by this proficient enzyme are extremely subtle.

Lietzan, Adam D.; Nagar, Mitesh; Pellmann, Elise A.; Bourque, Jennifer R.; Bearne, Stephen L.; Maurice, Martin St. (Dalhousie U.); (Marquette)

2012-05-09

28

Defunctionalized Lobeline Analogues: Structure–Activity of Novel Ligands for the Vesicular Monoamine Transporter  

PubMed Central

(?)-Lobeline (2R,6S,10S; 1a), an antagonist at nicotinic acetylcholine receptors (nAChRs), inhibits the neurochemical and behavioral effects of methamphetamine and inhibits dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2) function. VMAT2 is a target for the development of treatments for methamphetamine abuse. Structural modification of lobeline affords the defunctionalized analogues meso-transdiene (MTD) and lobelane, which have high potency and selectivity for VMAT2. To establish the structure–activity relationships within this novel class of VMAT2 ligands, specific stereochemical forms of MTD, lobelane, and other structurally related analogues have been synthesized. These compounds have been evaluated for inhibition of [3H]nicotine ([3H]NIC) binding (?4?2* nAChR), [3H]methyllycaconitine ([3H]MLA) binding (?7* nAChR), and [3H]dihydrotetrabenazine ([3H]DTBZ) binding (VMAT2). Generally, all of these analogues had lower affinities at ?4?2* and ?7* nAChRs compared to lobeline, thereby increasing selectivity for VMAT2. The following structural modifications resulted in only modest changes in affinity for VMAT2, affording analogues that were less potent than the lead compound, lobelane: (1) altering the stereochemistry at the C-2 and C-6 positions of the piperidino ring, (2) varying unsaturation in the piperidino C-2 and C-6 substituents, (3) introducing unsaturation into the piperidine ring, (4) ring-opening or eliminating the piperidine ring, and (5) removing the piperidino N-methyl group. Furthermore, incorporating a quaternary ammonium group into defunctionalized lobeline molecules in the cis-series resulted in significant loss of affinity for VMAT2, whereas only a modest change in affinity was obtained in the trans-series. The most potent (Ki = 630 nM) and VMAT2-selective compound evaluated was the N-methyl-2,6-cis-bis(naphthaleneethyl)piperidine analogue 28b (1-NAP-lobelane), in which the phenyl groups of lobelane were replaced with 1-naphthyl moieties. Thus, initial structure–activity relationship studies reveal that the most promising structural changes to the lobeline molecule that lead to enhancement of VMAT2 affinity and selectivity are defunctionalization, affording lobelane and MTD, and replacement of the phenyl rings of lobelane with other aromatic moieties that have a ?-extended structure. PMID:16107155

Zheng, Guangrong; Dwoskin, Linda P.; Deaciuc, Agripina G.; Norrholm, Seth D.; Crooks, Peter A.

2013-01-01

29

Characterization of electronic structure and physicochemical properties of antiparasitic nifurtimox analogues: A theoretical study  

NASA Astrophysics Data System (ADS)

American trypanosomiasis, also known as Chagas' disease, is caused by Trypanosoma cruzi (T. cruzi). It is well known that trypanosomes, and particularly T. cruzi, are highly sensitive towards oxidative stress, i.e., to compounds than are able to produce free radicals. Generally, nifurtimox (NFX) and benznidazol are most effective in the acute phase of the disease; therefore, nitroheterocycles constitute good models to design other nitrocompounds with specific biological characteristics. Thus, we have performed an ab initio study at the Hartree-Fock and Density Functional Theory levels of theory of several NFX analogues recently synthesized, to characterize them by obtaining their electronic, structural, and physicochemical properties, which might be linked to the observed antichagasic activity. The antitrypanosomal activity scale previously reported for the NFX analogues studied in this work is in good agreement with our theoretical results, from which we can conclude that the activity seems to be related to the reactivity along with the acidity observed for the most active molecules.

Soriano-Correa, Catalina; Raya, A.; Esquivel, Rodolfo O.

30

Design, synthesis, biological and structural evaluation of functionalized resveratrol analogues as inhibitors of quinone reductase 2  

PubMed Central

Resveratrol (3,5,4?-trihydroxylstilbene) has been proposed to elicit a variety of positive health effects including protection against cancer and cardiovascular disease. The highest affinity target of resveratrol identified so far is the oxidoreductase enzyme quinone reductase 2 (QR2), which is believed to function in metabolic reduction and detoxification processes; however, evidence exists linking QR2 to the metabolic activation of quinones, which can lead to cell toxicity. Therefore, inhibition of QR2 by resveratrol may protect cells against reactive intermediates and eventually cancer. With the aim of identifying novel inhibitors of QR2, we designed, synthesized, and tested two generations of resveratrol analogue libraries for inhibition of QR2. In addition, X-ray crystal structures of six of the resveratrol analogues in the active site of QR2 were determined. Several novel inhibitors of QR2 were successfully identified as well as a compound that inhibits QR2 with a novel binding orientation. PMID:23953689

St. John, Sarah E.; Jensen, Katherine C.; Kang, SooSung; Chen, Yafang; Calamini, Barbara; Mesecar, Andrew D.; Lipton, Mark A.

2013-01-01

31

Preparation, Structure, and Redox Behavior of Bis(diarylmethylene)dihydrothiophene and Its ?-Extended Analogues.  

PubMed

The preparation, X-ray structure, and optoelectronic properties of bis(diarylmethylene)dihydrothiophene 1 and its ?-extended analogues 2 are described. The development of a simple, short-step synthetic route allowed us to prepare derivatives with different aryl units. X-ray crystallographic analysis of 1b and 2b revealed their quinoidal structures, which exhibit strong electronic absorption in the visible region. Cyclic voltammetry measurements revealed their strong electron-donating properties. 1b showed two-step electrochromic behavior between the corresponding radical cation and dication. PMID:25634243

Takeda, Takashi; Akutagawa, Tomoyuki

2015-02-20

32

The Investigation of Structure-Activity Relationships of Tacrine Analogues: Electronic-Topological Method  

PubMed Central

In this study we investigated the structure-activity relationships by using the Electron- Topological Method (ETM) for a class of AChE inhibitors related to tacrine (9-amino-1,2,3,4-tetrahydroacridine) and 11 H-Indeno-[1,2-b]-quinolin-10-ylamine that tetracyclic tacrine analogues, a drug currently in use for the treatment of the AD. Molecular fragments being specific for active and inactive compounds were revealed by using ETM. The result of testing showed the high ability of ETM in predicting the activity and inactivity in investigated series. PMID:19662147

Saracoglu, Murat; Kandemirli, Fatma

2008-01-01

33

Naphthalene, Phenanthrene, and Pyrene as DNA Base Analogues: Synthesis, Structure, and Fluorescence in DNA  

PubMed Central

We describe the synthesis, structures, and DNA incorporation of deoxyribonucleosides carrying polycyclic aromatic hydrocarbons as the DNA “base” analogue. The new polycyclic compounds are 1-naphthyl, 2-naphthyl, 9-phenanthrenyl, and 1-pyrenyl deoxynucleosides. The compounds are synthesized using a recently developed C-glycosidic bond formation method involving organocadmium derivatives of the aromatic compounds coupling with a 1?-chlorodeoxyribose precursor. The principal products of this coupling are the ?-anomers of the deoxyribosides. An efficient method has also been developed for epimerization of the ?-anomers to ?-anomers by acid-catalyzed equilibration; this isomerization is successfully carried out on the four polycyclic nucleosides as well as two substituted phenyl nucleosides. The geometry of the anomeric substitution is derived from 1H NOE experiments and is also correlated with a single-crystal X-ray structure of one ?-isomer. Three of the polycyclic C-nucleoside derivatives are incorporated into DNA oligonucleotides via their phosphoramidite derivatives; the pyrenyl and phenanthrenyl derivatives are shown to be fluorescent in a DNA sequence. The results (1) broaden the scope of our C-glycoside coupling reaction, (2) demonstrate that (using a new acid-catalyzed epimerization) both ?- and ?-anomers are easily synthesized, and (3) constitute a new class of deoxynucleoside derivatives. Such nucleoside analogues may be useful as biophysical probes for the study of noncovalent interactions such as aromatic ?-stacking in DNA. In addition, the fluorescence of the phenanthrene and pyrene nucleosides may make them especially useful as structural probes. PMID:20865136

Ren, Rex X.-F.; Chaudhuri, Narayan C.; Paris, Pamela L.; Rumney, Squire; Kool, Eric T.

2009-01-01

34

Quad Trees: A Data Structure for Retrieval on Composite Keys  

Microsoft Academic Search

The quad tree is a data structure appropriate for storing information to be retrieved on composite keys. We discuss the specific case of two-dimensional retrieval, although the structure is easily generalised to arbitrary dimensions. Algorithms are given both for staightforward insertion and for a type of balanced insertion into quad trees. Empirical analyses show that the average time for insertion

Raphael A. Finkel; Jon Louis Bentley

1974-01-01

35

Inhibitory effects of caffeine analogues on neoplastic transformation: structure-activity relationship.  

PubMed

Some xanthine analogues, including 1,3,7-trimethylxanthine (caffeine) and 1,3-dimethylxanthine (theophylline), have been shown to exert anticancer activities in both cell culture and animal models. The present study focused on the relationship of structure and activity of 50 different caffeine analogues in preventing epidermal growth factor (EGF)-induced malignant transformation of mouse epidermal JB6 promotion-sensitive (P+) Cl41 (JB6 P+) cells. Results indicated that the inhibition of cell transformation by the 1,3,7-trialkylxanthines depends on the number of carbons at the alkyl groups R1 and R3, but not R7. Notably, 1-ethyl-3-hexylxanthine (xanthine 70) was the most effective compound for inhibiting EGF-induced neoplastic transformation among the 50 xanthine analogues tested. The 50% inhibition of cell transformation (ICT(50)) value for xanthine 70 was 48- or 75-fold less than the ICT(50) value of caffeine or theophylline, respectively. Further study revealed that xanthine 70 (5-40 muM) dose dependently inhibited EGF-induced transactivation of activator protein 1 (AP-1), whereas theophylline or caffeine (up to 500 muM) had no effect on AP-1 activity. In addition, xanthine 70 (10 muM) inhibited 12-O-tetradecanoylphorbol-13-acetate- or H-Ras-induced neoplastic transformation in JB6 P+ cells by 78.2 or 62.0%, respectively. Collectively, these results indicated that the number of carbons at R1 and R3 is important for the antitumor-promoting activity of the trialkylxanthines and xanthine 70 might be a promising anticancer agent. PMID:18195054

Rogozin, Evgeny A; Lee, Ki Won; Kang, Nam Joo; Yu, Haoyu; Nomura, Masaaki; Miyamoto, Ken-Ichi; Conney, Allan H; Bode, Ann M; Dong, Zigang

2008-06-01

36

Characterisation of structurally modified analogues of glucagon as potential glucagon receptor antagonists.  

PubMed

Acute in vitro and in vivo biological activities of four novel structural analogues of glucagon were tested. desHis(1)Pro(4)-glucagon, desHis(1)Pro(4)Glu(9)-glucagon, desHis(1)Pro(4)Glu(9)Lys(12)FA-glucagon and desHis(1)Pro(4)Glu(9)Lys(30)FA-glucagon were stable to DPP-4 degradation and dose-dependently inhibited glucagon-mediated cAMP production (p<0.05 to p<0.001). None stimulated insulin secretion in vitro above basal levels, but all inhibited glucagon-induced insulin secretion (p<0.01 to p<0.001). In normal mice all analogues antagonised acute glucagon-mediated elevations of blood glucose (p<0.05 to p<0.001) and blocked corresponding insulinotropic responses. In high-fat fed mice, glucagon-induced increases in plasma insulin (p<0.05 to p<0.001) and glucagon-induced hyperglycaemia were blocked (p<0.05 to p<0.01) by three analogues. In obese diabetic (ob/ob) mice only desHis(1)Pro(4)Glu(9)-glucagon effectively (p<0.05 to p<0.01) inhibited both glucagon-mediated glycaemic and insulinotropic responses. desHis(1)Pro(4)-glucagon and desHis(1)Pro(4)Glu(9)-glucagon were biologically ineffective when administered 8h prior to glucagon, whereas desHis(1)Pro(4)Glu(9)Lys(12)FA-glucagon retained efficacy (p<0.01) for up to 24h. Such peptide-derived glucagon receptor antagonists have potential for type 2 diabetes therapy. PMID:23891841

O'Harte, F P M; Franklin, Z J; Rafferty, E P; Irwin, N

2013-12-01

37

Cellular Localization of Dieldrin and Structure–Activity Relationship of Dieldrin Analogues in Dopaminergic Cells  

PubMed Central

The incidence of Parkinson’s disease (PD) correlates with environmental exposure to pesticides, such as the organochlorine insecticide, dieldrin. Previous studies found an increased concentration of the pesticide in the striatal region of the brains of PD patients and also that dieldrin adversely affects cellular processes associated with PD. These processes include mitochondrial function and reactive oxygen species production. However, the mechanism and specific cellular targets responsible for dieldrin-mediated cellular dysfunction and the structural components of dieldrin contributing to its toxicity (toxicophore) have not been fully defined. In order to identify the toxicophore of dieldrin, a structure–activity approach was used, with the toxicity profiles of numerous analogues of dieldrin (including aldrin, endrin, and cis-aldrin diol) assessed in PC6-3 cells. The MTT and lactate dehydrogenase (LDH) assays were used to monitor cell viability and membrane permeability after treatment with each compound. Cellular assays monitoring ROS production and extracellular dopamine metabolite levels were also used. Structure and stereochemistry for dieldrin were found to be very important for toxicity and other end points measured. Small changes in structure for dieldrin (e.g., comparison to the stereoisomer endrin) yielded significant differences in toxicity. Interestingly, the cis-diol metabolite of dieldrin was found to be significantly more toxic than the parent compound. Disruption of dopamine catabolism yielded elevated levels of the neurotoxin, 3,4-dihydroxyphenylacetaldehyde, for many organochlorines. Comparisons of the toxicity profiles for each dieldrin analogue indicated a structure-specific effect important for elucidating the mechanisms of dieldrin neurotoxicity. PMID:23763672

Allen, Erin M. G.; Florang, Virginia R.; Davenport, Laurie L.; Jinsmaa, Yunden; Doorn, Jonathan A.

2015-01-01

38

Band gap and chemically ordered domain structure of a graphene analogue BCN  

NASA Astrophysics Data System (ADS)

Chemically synthesized few layer graphene analogues of B xC yN z are characterized by aberration corrected transmission electron microscopy and high resolution electron energy loss spectroscopy (HREELS) to determine the local phase, electronic structure and band gap. HREELS band gap studies of a B xC yN z composition reveal absorption edges at 2.08, 3.43 and 6.01 eV, indicating that the B xC yN z structure may consist of domains of different compositions. The K-absorption edge energy position of the individual elements in B xC yN z is determined and compared with h-BN and graphite. An understanding of these experimental findings is developed with complementary first-principles based calculations of the various ordered configurations of B xC yN z.

Venu, K.; Kanuri, S.; Raidongia, K.; Hembram, K. P. S. S.; Waghmare, U. V.; Datta, R.

2010-12-01

39

Key Factors for Successful Generation of Protein–Fragment Structures  

Microsoft Academic Search

In the past two decades, fragment-based approaches have evolved as a predominant strategy in lead discovery. The availability of structural information on the interaction geometries of binding fragments is key to successful structure-guided fragment-to-lead evolution. In this chapter, we illustrate methodological advances for protein–fragment crystal structure generation in order to offer general lessons on the importance of fragment properties and

Jark Böttcher; Anja Jestel; Reiner Kiefersauer; Stephan Krapp; Susanna Nagel; Stefan Steinbacher; Holger Steuber

2011-01-01

40

Structural Basis for Recognition of Guanosine by a Synthetic Tricyclic Cytosine Analogue: Guanidinium G-Clamp  

SciTech Connect

An oligonucleotide analogue containing a novel heterocyclic analogue, the guanidinium G-clamp, was designed to allow formation of five H-bonds to guanosine. The guanidinium group was introduced postsynthetically by treatment of the deprotected oligonucleotide containing a free amino group with a solution of 1H-pyrazole-1-carboxamidine and purified by a combination of size-exclusion chromatography and reversed-phase HPLC. A single incorporation of this modification into an oligodeoxynucleotide sequence was found to increase duplex stability by 13{sup o} and 16{sup o} per modification to RNA and DNA, respectively. Crystals of a self-complementary decamer sequence containing this modification were grown and diffracted to 1-{angstrom} resolution. The structure was solved by molecular replacement and revealed that the modification forms additional H-bonds to O(6) and N(7) of guanosine through the amino and imino N-atoms, respectively. The origins of enhanced duplex stability are also attributed to increased stacking interactions mediated by the phenoxazine moiety of the G-clamp and formation of H-bond networks between the positively charged guanidinium group, H{sub 2}O molecules, and negatively charged O-atoms from phosphates on the adjacent strand.

Wilds, C.J.; Maier, M.A.; Manoharan, M.; Egli, M.

2010-03-08

41

Extrapolating surface structures to depth in transpressional systems: the role of rheology and convergence angle deduced from analogue experiments  

NASA Astrophysics Data System (ADS)

The internal structure of major strike-slip faults is still poorly understood, particularly how the deep structure could be inferred from its surface expression (Molnar and Dayem, 2011 and references therein). Previous analogue experiments suggest that the convergence angle is the most influential factor (Leever et al., 2011). Further analogue modeling may allow a better understanding how to extrapolate surface structures to the subsurface geometry of strike-slip faults. Various scenarios of analogue experiments were designed to represent strike-slip faults in nature from different geological settings. As such key parameters, which are investigated in this study include: (a) the angle of convergence, (b) the thickness of brittle layer, (c) the influence of a rheological weak layer within the crust, and (d) influence of a thick and rheologically weak layer at the base of the crust. The latter aimed to simulate the effect of a hot metamorphic core complex or an alignment of uprising plutons bordered by a transtensional/transpressional strike-slip fault. The experiments are aimed to explain first order structures along major transcurrent strike-slip faults such as the Altyn, Kunlun, San Andrea and Greendale (Darfield earthquake 2010) faults. The preliminary results show that convergence angle significantly influences the overall geometry of the transpressive system with greater convergence angles resulting in wider fault zones and higher elevation. Different positions, densities and viscosities of weak rheological layers have not only different surface expressions but also affect the fault geometry in the subsurface. For instance, rheological weak material in the bottom layer results in stretching when experiment reaches a certain displacement and a buildup of a less segmented, wide positive flower structure. At the surface, a wide fault valley in the middle of the fault zone is the reflection of stretching along the velocity discontinuity at depth. In models with a thin and rheologically weaker layer in the middle of the brittle layer, deformation is distributed over more faults and the geometry of the fault zone below and above the weak zone shows significant differences, suggesting that the correlation of structures across a weak layer has to be supported by geophysical data, which help constraining the geometry of the deep part. This latter experiment has significantly similar phenomena in reality, such as few pressure ridges along Altyn fault. The experimental results underline the need to understand the role of the convergence angle and the influence of rheology on fault evolution, in order to connect between surface deformation and subsurface geometry. References Leever, K. A., Gabrielsen, R. H., Sokoutis, D., Willingshofer, E., 2011. The effect of convergence angle on the kinematic evolution of strain partitioning in transpressional brittle wedges: Insight from analog modeling and high-resolution digital image analysis. Tectonics, 30(2), TC2013. Molnar, P., Dayem, K.E., 2010. Major intracontinental strike-slip faults and contrasts in lithospheric strength. Geosphere, 6, 444-467.

Hsieh, Shang Yu; Neubauer, Franz; Cloetingh, Sierd; Willingshofer, Ernst; Sokoutis, Dimitrios

2014-05-01

42

Interaction of ascending magma with pre-existing crustal structures: Insights from analogue modeling  

NASA Astrophysics Data System (ADS)

Magma transport through dikes is a major component of the development of basaltic volcanic fields. Basaltic volcanic fields occur in many different tectonic setting, from tensile (e.g., Camargo Volcanic Field, Mexico) to compressive (e.g., Abu Monogenetic Volcano Group, Japan). However, an important observation is that, independently of their tectonic setting, volcanic fields are characterized by numerous volcanic centers showing clustering and lineaments, each volcanic center typically resulting from a single main eruption. Analyses from Auckland Volcanic Field reveal that, for each eruption, magma was transported from its source and reached the surface at different places within the same field, which raises the important question of the relative importance of 1) the self-propagation of magma through pristine rock, as opposed to 2) the control exerted by pre-existing structures. These two mechanisms have different implications for the alignment of volcanic centers in a field as these may reflect either 1) the state of crustal stress dikes would have experienced (with a tendency to propagate perpendicular to the least compressive stress) or 2) the interaction of propagating dikes with pre-existing crustal faults. In the latter case, lineaments might not be related to the syn-emplacement state of stress of the crust. To address this issue, we have carried out a series of analogue experiments in order to constrain the interaction of a propagating magma-filled dike with superficial pre-existing structures (e.g., fracture, fault, joint system). The experiments involved the injection of air (a buoyant magma analogue) into elastic gelatine solids (crustal rock analogues). Cracks were cut into the upper part of the gelatine solids prior to the injection of air to simulate the presence of pre-existing fractures. The volume of the propagating dikes, their distance from pre-existing fractures and the ambient stress field were systematically varied to assess their influence on the propagating dikes and their potential interaction with pre-existing fractures. The experimental results will be presented and discussed in the context of basaltic field volcanism before relating them to Auckland Volcanic Field.

Le Corvec, N.; Menand, T.; Rowland, J. V.

2010-12-01

43

Impact of synkinematic sedimentation on the geometry and dynamics of compressive growth structures: Insights from analogue modelling  

NASA Astrophysics Data System (ADS)

Analogue sandbox models have been set up to study the impact of synkinematic deposits on the geometry and evolution of single thrusts and folds according to different sedimentation modes (a slow or rapid sedimentation rate that is constant or changing in space and time) and rheological profiles (thin or thick sedimentary series, with or without a basal décollement level). A first series of experiments documents the influence of synkinematic deposits according to their sedimentation rate and the rheology of the prekinematic materials. A second series investigates the influence of changes in the sedimentation rate through time. A third one considers the influence of changes in the sedimentation rate in space. All these experiments suggest that the geometry and evolution of single compressive growth structures vary according to the sedimentation rate. The number and dip of their frontal thrust segments change with the ratio R between the sedimentation rate at the footwall of the faults and the uplift rate of their hanging wall. The latter is then more or less uplifted depending on the dip of the thrusts. As a result, the overall structure has either a fault-bend fold or a fault-propagation fold geometry. These rules are verified when the ratio R changes in space or through time. In addition, the rheological profile of the models also affects the geometry and evolution of compressive growth structures. Their structural style, as well as the synsedimentary splitting and steepening of the associated thrusts, varies according to the occurrence and strength of the brittle and ductile layers. According to this modelling study, the ratio R and its changes in space and time, along with the rheology of the deformed materials, are key parameters to better understand the geometrical and kinematical complexities of natural growth thrusts and folds and to improve their interpretation.

Barrier, Laurie; Nalpas, Thierry; Gapais, Denis; Proust, Jean-Noël

2013-11-01

44

Structural Insight into Methyl-Coenzyme M Reductase Chemistry Using Coenzyme B Analogues  

SciTech Connect

Methyl-coenzyme M reductase (MCR) catalyzes the final and rate-limiting step in methane biogenesis: the reduction of methyl-coenzyme M (methyl-SCoM) by coenzyme B (CoBSH) to methane and a heterodisulfide (CoBS-SCoM). Crystallographic studies show that the active site is deeply buried within the enzyme and contains a highly reduced nickel-tetrapyrrole, coenzyme F430. Methyl-SCoM must enter the active site prior to CoBSH, as species derived from methyl-SCoM are always observed bound to the F430 nickel in the deepest part of the 30 {angstrom} long substrate channel that leads from the protein surface to the active site. The seven-carbon mercaptoalkanoyl chain of CoBSH binds within a 16 {angstrom} predominantly hydrophobic part of the channel close to F430, with the CoBSH thiolate lying closest to the nickel at a distance of 8.8 {angstrom}. It has previously been suggested that binding of CoBSH initiates catalysis by inducing a conformational change that moves methyl-SCoM closer to the nickel promoting cleavage of the C-S bond of methyl-SCoM. In order to better understand the structural role of CoBSH early in the MCR mechanism, we have determined crystal structures of MCR in complex with four different CoBSH analogues: pentanoyl, hexanoyl, octanoyl, and nonanoyl derivatives of CoBSH (CoB5SH, CoB6SH, CoB8SH, and CoB9SH, respectively). The data presented here reveal that the shorter CoB5SH mercaptoalkanoyl chain overlays with that of CoBSH but terminates two units short of the CoBSH thiolate position. In contrast, the mercaptoalkanoyl chain of CoB6SH adopts a different conformation, such that its thiolate is coincident with the position of the CoBSH thiolate. This is consistent with the observation that CoB6SH is a slow substrate. A labile water in the substrate channel was found to be a sensitive indicator for the presence of CoBSH and HSCoM. The longer CoB8SH and CoB9SH analogues can be accommodated in the active site through exclusion of this water. These analogues react with Ni(III)-methyl, a proposed MCR catalytic intermediate of methanogenesis. The CoB8SH thiolate is 2.6 {angstrom} closer to the nickel than that of CoBSH, but the additional carbon of CoB9SH only decreases the nickel thiolate distance a further 0.3 {angstrom}. Although the analogues do not induce any structural changes in the substrate channel, the thiolates appear to preferentially bind at two distinct positions in the channel, one being the previously observed CoBSH thiolate position and the other being at a hydrophobic annulus of residues that lines the channel proximal to the nickel.

Cedervall, Peder E.; Dey, Mishtu; Pearson, Arwen R.; Ragsdale, Stephen W.; Wilmot, Carrie M. (Michigan); (UMM)

2010-09-07

45

[Structure-activity relationship of novel vitamin K analogues as steroid and xenobiotic receptor (SXR) agonists].  

PubMed

Vitamin K2 is a ligand for a nuclear receptor, steroid and xenobiotic receptor (SXR), that induces the gene expressions of CYP3A4. We synthesized new vitamin K analogues with the same isoprene side chains symmetrically introduced at the 2 and 3 positions of 1,4-naphthoquinone and vitamin K2 analogues with hydroxyl or phenyl groups at the ?-terminal of the side chain. The upregulation of SXR-mediated transcription of the target gene by the analogues was dependent on the length of the side chain and the hydrophobicity of the ?-terminal residues. Phenyl analogue menaquinone-3 was as active as the known SXR ligand rifampicin. PMID:22864345

Suhara, Yoshitomo; Motoyoshi, Sayaka; Hirota, Yoshihisa; Sawada, Natsumi; Nakagawa, Kimie; Tokiwa, Hiroaki; Okano, Toshio

2012-01-01

46

Morpho-structural criteria for the identification of volcano deformation processes from analogue modeling  

NASA Astrophysics Data System (ADS)

The morphology of volcanoes provides important information about edifice evolution. Volcanoes can deform by gravitational instability and intrusions. This deformation can compromise volcano structural stability, promoting flank collapse even at dormant edifices. Identification of past/active deformation processes is therefore important not only for the understanding of volcano evolution but also for volcanic hazards. Both deformation due to the flank spreading of a volcano over its weak core and due to the intrusion of a cryptodome in the volcano edifice can produce faulting and changes in the morphology of volcano flanks. These morpho-structural changes in the volcano open the possibility to identify potential deformed and unstable volcanoes using remote sensing techniques and DEMs. We have used analogue models of flank spreading and intrusion processes to make progress in the morpho-structural identification of deformation features which can provide criteria for distinguishing processes. We have geometrically and mechanically scaled two different sets of experiments using a sand-plaster mixture for volcano materials, silicone putty for weak core rocks and Golden Syrup for magma intrusions. For monitoring changes in the volcano morphology we have used a Kinect sensor (Microsoft), which provides us vertical displacements of volcano flanks several times per second with a 1 mm precision. We have synchronized the Kinect sensor with a digital camera for monitoring the spatio-temporal evolution of tectonic structures together with morphology. All experiments produce asymmetrical changes in volcano morphology, developing convex-concave geometries in the deformed flank. However, the spatial relationships of structures with changes in volcano flank curvature are different for the two processes, as noted by previous authors. The morphometric tools developed for analyzing volcano topography allow us to identify intrusion processes due to volcano volume increase. We have compared the results of our experiments with known examples of deformed volcanoes due to intrusions (eg., St Helens) and flank spreading (eg. Casita) and we confirmed that the criteria developed from modeling works well in the natural cases. We consider that further experiments are necessary to fully explore the capacity of application of morphometric tools to analogue modeling of volcano deformation processes, since our first results show a promising research avenue for the remote identification and evaluation of volcano deformation processes in remote volcanoes worldwide.

Rincon, Marta; Marquez, Alvaro; van Wyk de Vries, Benjamin; Herrera, Raquel; Granja Bruña, Jose Luis; Llanes, Pilar

2014-05-01

47

New structural analogues of curcumin exhibit potent growth suppressive activity in human colorectal carcinoma cells  

PubMed Central

Background Colorectal carcinoma is one of the major causes of morbidity and mortality in the Western World. Novel therapeutic approaches are needed for colorectal carcinoma. Curcumin, the active component and yellow pigment of turmeric, has been reported to have several anti-cancer activities including anti-proliferation, anti-invasion, and anti-angiogenesis. Clinical trials have suggested that curcumin may serve as a potential preventive or therapeutic agent for colorectal cancer. Methods We compared the inhibitory effects of curcumin and novel structural analogues, GO-Y030, FLLL-11, and FLLL-12, in three independent human colorectal cancer cell lines, SW480, HT-29, and HCT116. MTT cell viability assay was used to examine the cell viability/proliferation and western blots were used to determine the level of PARP cleavages. Half-Maximal inhibitory concentrations (IC50) were calculated using Sigma Plot 9.0 software. Results Curcumin inhibited cell viability in all three of the human colorectal cancer cell lines studied with IC50 values ranging between 10.26 ?M and 13.31 ?M. GO-Y030, FLLL-11, and FLLL-12 were more potent than curcumin in the inhibition of cell viability in these three human colorectal cancer cell lines with IC50 values ranging between 0.51 ?M and 4.48 ?M. In addition, FLLL-11 and FLLL-12 exhibit low toxicity to WI-38 normal human lung fibroblasts with an IC-50 value greater than 1,000 ?M. GO-Y030, FLLL-11, and FLLL-12 are also more potent than curcumin in the induction of apoptosis, as evidenced by cleaved PARP and cleaved caspase-3 in all three human colorectal cancer cell lines studied. Conclusion The results indicate that the three curcumin analogues studied exhibit more potent inhibitory activity than curcumin in human colorectal cancer cells. Thus, they may have translational potential as chemopreventive or therapeutic agents for colorectal carcinoma. PMID:19331692

2009-01-01

48

Antigelling and antisickling bisphenyl oligopeptides and peptide analogues have similar structural features.  

PubMed

Single-crystal X-ray diffraction was used to determine the three-dimensional structures of two antigelling oligopeptides, L-lysyl-L-phenylalanyl-L-phenylalanine and L-phenylalanylglycylglycyl-D-phenylalanine, and two antisickling peptide analogues, L-phenylalanine benzyl ester and N-phenylacetyl-L-phenylalanine. Although these bisphenyl compounds are chemically quite different from one another, they demonstrate unusual structural similarities: The molecules have compact conformations in which the two phenyl rings are positioned approximately 5 A apart with interplanar angles approaching 90 degrees, thereby making intramolecular edge-to-face interactions. In addition, the polar atoms, nitrogen and oxygen, are in close proximity without forming intramolecular hydrogen bonds. The relative spatial distribution of polar and nonpolar atoms renders the structures compact and amphipathic. The intramolecular edge-to-face interaction between two aromatic rings, which brings a hydrogen atom with relative positive charge near the pi-electron cloud with relative negative charge, is enthalpically favorable and maintains the molecules in a compact and amphipathic conformation. Nonbonded potential energy calculations were used to characterize the energetics of the aromatic-aromatic interaction, and they showed that the observed geometry is stabilized enthalpically by a favorable interaction on the order of -1 to -2 kcal/mol. Structural differences between the two antisickling and the two antigelling agents suggest that molecular volume limits red cell membrane passage. These data provide a molecular structural framework from which to design and synthesize amphipathic bisphenyl compounds that both bind to deoxy sickle cell hemoglobin and cross the erythrocyte membrane. PMID:3663644

Burley, S K; Wang, A H; Votano, J R; Rich, A

1987-08-11

49

Intercalation of antitumor drug doxorubicin and its analogue by DNA duplex: structural features and biological implications.  

PubMed

The intercalation of antitumor drug doxorubicin (DOX) and its analogue N-(trifluoroacetyl) doxorubicin (FDOX) with DNA duplex was investigated, using FTIR, CD, fluorescence spectroscopic methods and molecular modeling. Both DOX and FDOX were intercalated into DNA duplex with the free binding energy of -4.99 kcal for DOX-DNA and -4.92 kcal for FDOX-DNA adducts and the presence of H-bonding network between doxorubicin NH2 group and cytosine-19. Spectroscopic results showed FDOX forms more stable complexes than DOX with KDOX-DNA=2.5(± 0.5)× 10(4)M(-1) and KFDOX-DNA=3.4(± 0.7)× 10(4)M(-1). The number of drug molecules bound per DNA (n) was 1.2 for DOX and 0.6 for FDOX. Major alterations of DNA structure were observed by DOX intercalation with a partial B to A-DNA transition, while no DNA conformational changes occurred upon FDOX interaction. This study further confirms the importance of unmodified daunosamine amino group for optimal interactions with DNA. The results of in vitro MTT assay carried out on SKC01 colon carcinoma corroborate the observed DNA interactions. Such DNA structural changes can be related to doxorubicin antitumor activity, which prevents DNA duplication. PMID:24560949

Agudelo, Daniel; Bourassa, Philippe; Bérubé, Gervais; Tajmir-Riahi, Heidar-Ali

2014-05-01

50

Sandbox analogue modeling of strike-slip crustal shear zones involving structural inheritance  

NASA Astrophysics Data System (ADS)

Structural inheritance is widely recognized as an important factor that contributes to determine the architecture of newly developing tectonic systems, including the possibility to trigger otherwise unexpected intraplate deformations. This has important implications for seismic hazard, for plate tectonic reconstructions, and for the possible occurrence of new petroleum plays. Properly scaled analogue models provide a useful tool to investigate geological processes by simulating their dynamic and kinematic evolution. We present results of a sandbox experimental programme designed to investigate the influence of structural inheritance on the evolution and tectonic architecture of crustal-scale strike-slip fault systems. Two layers of quartz sand and silicon putty were used to simulate the rheological behavior of the upper and lower crust, respectively. Different pre-deformational configurations of inherited, mechanically weaker zones were tested by inserting silicone stripes in the lower half of the upper sand layer. Results indicate a significant impact of inherited weakness zones on the 3D geometry and time evolution of experimental strike-slip fault systems.

Nestola, Y.; Cavozzi, C.; Cella, M.; Magistroni, C.; Salvi, F.; Spadini, G.; Storti, F.

2012-04-01

51

Analogue modelling of rock avalanches and structural analysis of the deposits  

NASA Astrophysics Data System (ADS)

Rock avalanches are catastrophic events in which granular masses of rock debris flow at high speeds, commonly with unusual runout. A great volume of material (>106 m3) is involved and the flowing mass can reach velocities up to ten meters per second. Rock avalanches can travel long distances on the order of kilometres and covering an area over 0.1 km2. These are extremely destructive and uncontrollable events. Due to the rarity of these events, analogue modelling plays a fundamental role in the understanding of the behaviour such events. The main objective of this research is to link the granular physics with the modelling of rock avalanches. Firstly, we attempt to model the debris avalanche and its spreading on a slope with different substratum to understand the relationship between the volume and the reach angle, or Fahrböschung, i.e. angle of the line joining the top of the scar and the end of the deposit. For a better understanding of the sliding mass motion and its spreading, the deposit is scanned with a micro Lidar Minolta. The different datasets are compared in order to see how the grainsize and volume influence a debris avalanche. In a general way, the travel distance is greater with coarse material and varies between 32° for the coarser grainsize and 37° for the finer one. It is interesting to note that the highest Fahrböschung, 41°, is reached for the highest slope angle (60°) and varies between 32 and 34.5° for a slope of 40°. Secondly, a detailed structural analysis of the deposit is performed in order to understand how the sliding mass stops. Several authors (e.g. Shea and van Wyk de Vries (2008)) highlighted that faults and folds are present in rock avalanches deposits and reproduced these features in analogue modelling. Our experiments are recorded by a height speed precision camera to see the development of these structures during the flowing of the mass. The most important impacts of this study is a better understanding of the effects of grainsize, substratum and material type on the behaviour of rock avalanches regarding the density of material and basal friction angle. If the behaviour of those debris avalanches is better understood, the prediction and the risk assessment for such events will be better constrained.

Longchamp, C.; Charrière, M.; Jaboyedoff, M.

2012-04-01

52

Carbocyclic nucleoside analogues: classification, target enzymes, mechanisms of action and synthesis  

NASA Astrophysics Data System (ADS)

Key biological targets (S-adenosyl-L-homocysteine hydrolase, telomerase, human immunodeficiency virus reverse transcriptase, herpes virus DNA polymerase and hepatitis B virus DNA polymerase) and the mechanisms of action of carbocyclic nucleoside analogues are considered. Structural types of analogues are discussed. Methods of synthesis for the most promising compounds and the spectrum of their biological activities are described. The bibliography includes 126 references.

Matyugina, E. S.; Khandazhinskaya, A. P.; Kochetkov, Sergei N.

2012-08-01

53

Structural and Functional Characterization of a Multifunctional Alanine-Rich Peptide Analogue from Pleuronectes americanus  

PubMed Central

Recently, defense peptides that are able to act against several targets have been characterized. The present work focuses on structural and functional evaluation of the peptide analogue Pa-MAP, previously isolated as an antifreeze peptide from Pleuronectes americanus. Pa-MAP showed activities against different targets such as tumoral cells in culture (CACO-2, MCF-7 and HCT-116), bacteria (Escherichia coli ATCC 8739 and Staphylococcus aureus ATCC 25923), viruses (HSV-1 and HSV-2) and fungi (Candida parapsilosis ATCC 22019, Trichophyton mentagrophytes (28d&E) and T. rubrum (327)). This peptide did not show toxicity against mammalian cells such as erythrocytes, Vero and RAW 264.7 cells. Molecular mechanism of action was related to hydrophobic residues, since only the terminal amino group is charged at pH 7 as confirmed by potentiometric titration. In order to shed some light on its structure-function relations, in vitro and in silico assays were carried out using circular dichroism and molecular dynamics. Furthermore, Pa-MAP showed partial unfolding of the peptide changes in a wide pH (3 to 11) and temperature (25 to 95°C) ranges, although it might not reach complete unfolding at 95°C, suggesting a high conformational stability. This peptide also showed a conformational transition with a partial ?-helical fold in water and a full ?-helical core in SDS and TFE environments. These results were corroborated by spectral data measured at 222 nm and by 50 ns dynamic simulation. In conclusion, data reported here show that Pa-MAP is a potential candidate for drug design against pathogenic microorganisms due to its structural stability and wide activity against a range of targets. PMID:23056574

Migliolo, Ludovico; Silva, Osmar N.; Silva, Paula A.; Costa, Maysa P.; Costa, Carolina R.; Nolasco, Diego O.; Barbosa, João A. R. G.; Silva, Maria R. R.; Bemquerer, Marcelo P.; Lima, Lidia M. P.; Romanos, Maria T. V.; Freitas, Sonia M.; Magalhães, Beatriz S.; Franco, Octavio L.

2012-01-01

54

Spectroscopic, thermal and single crystal structure investigations of 2-bromotrimesic acid and its trimethyl ester analogue  

NASA Astrophysics Data System (ADS)

Two analogues of the well investigated trimesic acid viz. the 2-bromobenzene-1,3,5-tricarboxylic acid 1 and their ester trimethyl 2-bromobenzene-1,3,5-tricarboxylate 2, have been synthesised and their X-ray structures were solved. Acid 1 crystallises as 1:1 inclusion compound with water in a layer structure. Like in the solid state structure of trimesic acid, we found strong Osbnd H???O hydrogen bonds between one of the carboxyl groups and a neighbouring molecule to form a hydrogen bonding motif R22(8). Additionally, a water molecule and a second acid function of 1 are involved in further hydrogen bonding featuring the graph set R44(12) forming what might be called a water inserted dimer. As shown by TG-DSC measurements the water molecule in the 1:1 inclusion compound of 1 is engaged in two strong Osbnd H???O hydrogen bonds, it escapes at a rather low temperature of 99 °C. Bromine monosubstitution at the benzene ring forces the third carboxylic acid out of the mean plane of the molecule, which disturbs the coplanar arrangement of the three COOH moieties. Thus, the typical “chicken-wire” network formation is hindered. In the trimethyl 2-bromobenzene-1,3,5-tricarboxylate (2), the formation of strong Osbnd H???O hydrogen bonds is disabled by esterification of the acid functions. Nevertheless, the packing of 2 features solvent free molecular layers formed by Br???O contacts and connected van der Waals interactions. These layers are linked to each other by inverse bifurcated hydrogen bonds in term weak Csbnd H???O contacts. The results of the X-ray analysis could be confirmed by infrared spectroscopy.

Münch, Alexander S.; Katzsch, Felix; Gruber, Tobias; Mertens, Florian O. R. L.

2014-09-01

55

Structure of the cytochrome b6f complex: quinone analogue inhibitors as ligands of heme cn.  

PubMed

A native structure of the cytochrome b(6)f complex with improved resolution was obtained from crystals of the complex grown in the presence of divalent cadmium. Two Cd(2+) binding sites with different occupancy were determined: (i) a higher affinity site, Cd1, which bridges His143 of cytochrome f and the acidic residue, Glu75, of cyt b(6); in addition, Cd1 is coordinated by 1-2 H(2)O or 1-2 Cl(-); (ii) a second site, Cd2, of lower affinity for which three identified ligands are Asp58 (subunit IV), Glu3 (PetG subunit) and Glu4 (PetM subunit). Binding sites of quinone analogue inhibitors were sought to map the pathway of transfer of the lipophilic quinone across the b(6)f complex and to define the function of the novel heme c(n). Two sites were found for the chromone ring of the tridecyl-stigmatellin (TDS) quinone analogue inhibitor, one near the p-side [2Fe-2S] cluster. A second TDS site was found on the n-side of the complex facing the quinone exchange cavity as an axial ligand of heme c(n). A similar binding site proximal to heme c(n) was found for the n-side inhibitor, NQNO. Binding of these inhibitors required their addition to the complex before lipid used to facilitate crystallization. The similar binding of NQNO and TDS as axial ligands to heme c(n) implies that this heme utilizes plastoquinone as a natural ligand, thus defining an electron transfer complex consisting of hemes b(n), c(n), and PQ, and the pathway of n-side reduction of the PQ pool. The NQNO binding site explains several effects associated with its inhibitory action: the negative shift in heme c(n) midpoint potential, the increased amplitude of light-induced heme b(n) reduction, and an altered EPR spectrum attributed to interaction between hemes c(n) and b(n). A decreased extent of heme c(n) reduction by reduced ferredoxin in the presence of NQNO allows observation of the heme c(n) Soret band in a chemical difference spectrum. PMID:17498743

Yamashita, E; Zhang, H; Cramer, W A

2007-06-29

56

The Manicouagan impact structure as a terrestrial analogue site for lunar and martian planetary science  

NASA Astrophysics Data System (ADS)

The 90 km diameter, late Triassic Manicouagan impact structure of Québec, Canada, is a well-preserved, undeformed complex crater possessing an anorthositic central uplift and a 55 km diameter melt sheet. As such, it provides a valuable terrestrial analogue for impact structures developed on other planetary bodies, especially the Moon and Mars, which are currently the focus of exploration initiatives. The scientific value of Manicouagan has recently been enhanced due to the production, between 1994 and 2006, of ˜18 km of drill core from 38 holes by the mineral exploration industry. Three of these holes are in excess of 1.5 km deep, with the deepest reaching 1.8 km. Here we combine recent field work, sampling and the drill core data with previous knowledge to provide insight into processes occurring at Manicouagan and, by inference, within extraterrestrial impact structures. Four areas of comparative planetology are discussed: impact melt sheets, central uplifts, impact-generated hydrothermal regimes and footwall breccias. Human training and instrument testing opportunities are also considered. The drill core reveals that the impact melt and clast-bearing impact melts in the centre of the structure reach thicknesses of 1.4 km. The 1.1 km thick impact melt has undergone differentiation to yield a lower monzodiorite, a transitional quartz monzodiorite and an upper quartz monzonite sequence. This calls into question the previous citing of Manicouagan as an exemplar of a relatively large crater possessing an undifferentiated melt sheet, which was used as a rationale for assigning different composition lunar impact melts and clast-bearing impact melts to separate cratering events. The predominantly anorthositic central uplift at Manicouagan is comparable to certain lunar highlands material, with morphometric analogies to the King, Tycho, Pythagoras, Jackson, and Copernicus impact structures, which have similar diameters and uplift structure. Excellent exposure of the Manicouagan uplift facilitates mapping and an appraisal of its formation and collapse mechanisms, enhanced by drill core data from the centre of the structure. Recent field studies at the edge of the central island at Manicouagan, and multiple drill core sections through footwall lithologies, provide insight into allochthonous (clastic and suevitic) and autochthonous breccia formation, as well as shock effects. The hydrothermal regimes developed at Manicouagan are akin to systems proposed for Noachian (>3.5 Ga) Mars that involve alteration of impact melts via meteoritic and surface waters, with the generation of phyllosilicates, zeolites, hematite, sulfates and sulfides that can contribute to martian soil formation and sedimentation processes.

Spray, John G.; Thompson, Lucy M.; Biren, Marc B.; O'Connell-Cooper, Catherine

2010-03-01

57

Mutagenicity and DNA damage of bisphenol A and its structural analogues in HepG2 cells.  

PubMed

Environmental oestrogen bisphenol A (BPA) and its analogues are widespread in our living environment. Because their production and use are increasing, exposure of humans to bisphenols is becoming a significant issue. We evaluated the mutagenic and genotoxic potential of eight BPA structural analogues (BPF, BPAF, BPZ, BPS, DMBPA, DMBPS, BP-1, and BP-2) using the Ames and comet assay, respectively. None of the tested bisphenols showed a mutagenic effect in Salmonella typhimurium strains TA98 and TA100 in either the presence or absence of external S9-mediated metabolic activation (Aroclor 1254-induced male rat liver). Potential genotoxicity of bisphenols was determined in the human hepatoma cell line (HepG2) at non-cytotoxic concentrations (0.1 ?mol L(-1) to 10 ?mol L(-1)) after 4-hour and 24-hour exposure. In the comet assay, BPA and its analogue BPS induced significant DNA damage only after the 24-hour exposure, while analogues DMBPS, BP-1, and BP-2 induced a transient increase in DNA strand breaks. PMID:23819927

Fic, Anja; Žegura, Bojana; Sollner Dolenc, Marija; Filipi?, Metka; Peterlin Maši?, Lucija

2013-06-01

58

Elucidation of Structural Elements for Selectivity across Monoamine Transporters: Novel 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues  

PubMed Central

2-[(Diphenylmethyl)sulfinyl]acetamide (modafinil, (±)-1) is a unique dopamine uptake inhibitor that binds the dopamine transporter (DAT) differently than cocaine and may have potential for the treatment of psychostimulant abuse. To further investigate structural requirements for this divergent binding mode, novel thio- and sulfinylacetamide and ethanamine analogues of (±)-1 were synthesized wherein (1) the diphenyl rings were substituted with methyl, trifluoromethyl, and halogen substituents and (2) substituents were added to the terminal amide/amine nitrogen. Halogen substitution of the diphenyl rings of (±)-1 gave several amide analogues with improved binding affinity for DAT and robust selectivity over the serotonin transporter (SERT), whereas affinity improved at SERT over DAT for the p-halo-substituted amine analogues. Molecular docking studies, using a subset of analogues with DAT and SERT homology models, and functional data obtained with DAT (A480T) and SERT (T497A) mutants defined a role for TM10 in the substrate/inhibitor S1 binding sites of DAT and SERT. PMID:24494745

2015-01-01

59

Nucleic acid-like structures II. Polynucleotide analogues as possible primitive precursors of nucleic acids  

Microsoft Academic Search

Activated derivatives of purine-containing deoxynucleoside- diphosphates spontaneously oligomerize to produce pyrophosphate-\\u000a linked oligodeoxynucleotide analogues. These analogues are of potential interest as models of primitive, polynucleotide precursors.\\u000a The efficiency of oligomerization (ImpdGpIm and ImpdApIm much greater than ImpdIpIm) appears to reflect a combination of stacking\\u000a forces and the specific geometric orientations of the stacked units. Under favorable conditions, chain lengths greater

Alan W. Schwartz; J. Visscher; C. G. Bakker; J. Niessen

1987-01-01

60

Biofunctional constituent isolated from Citrullus colocynthis fruits and structure-activity relationships of its analogues show acaricidal and insecticidal efficacy.  

PubMed

The acaricidal and insecticidal potential of the active constituent isolated from Citrullus colocynthis fruits and its structurally related analogues was evaluated by performing leaf disk, contact toxicity, and fumigant toxicity bioassays against Tetranychus urticae, Sitophilus oryzae, and Sitophilus zeamais adults. The active constituent of C. colocynthis fruits was isolated by chromatographic techniques and was identified as 4-methylquinoline on the basis of spectroscopic analyses. To investigate the structure-activity relationships, 4-methylquinoline and its structural analogues were tested against mites and two insect pests. On the basis of the LC50 values, 7,8-benzoquinoline was the most effective against T. urticae. Quinoline, 8-hydroxyquinoline, 2-methylquinoline, 4-methylquinoline, 6-methylquinoline, 8-methylquinoline, and 7,8-benzoquinoline showed high insecticidal activities against S. oryzae and S. zeamais regardless of the application method. These results indicate that introduction of a functional group into the quinoline skeleton and changing the position of the group have an important influence on the acaricidal and insecticidal activities. Furthermore, 4-methylquinoline isolated from C. colocynthis fruits, along with its structural analogues, could be effective natural pesticides for managing spider mites and stored grain weevils. PMID:25110971

Jeon, Ju-Hyun; Lee, Hoi-Seon

2014-08-27

61

The Grid File: An Adaptable, Symmetric Multi-Key File Structure  

Microsoft Academic Search

Traditional file structures that provide multi-key access to records, for example inverted files, are extensions of file structures originally designed for single-key access. They manifest various deficiencies, in particular for multi-key access to highly dynamic files. We study the dynamic aspects of file structures that treat all keys symmetrically, that is, avoid the distinction between primary key and secondary keys.

Jürg Nievergelt; Hans Hinterberger; Kenneth C. Sevcik

1981-01-01

62

Novel and efficient syntheses of (-)-methyl 4-epi-shikimate and 4,5-epoxy-quinic and -shikimic acid derivatives as key precursors to prepare new analogues.  

PubMed

We have developed simple methods that provide a rapid entry into the synthesis of a series of quinate and shikimate analogues, including (-)-methyl 4-epi-shikimate and the 4,5-epoxy analogues of the parent acids. Epoxy derivatives of quinic and shikimic acids were converted into methyl scyllo-quinate and (+)-methyl 3-epi-shikimate, respectively, by processes involving a regio- and stereoselective epoxide ring opening. The strategies described take place through short, high-yield reaction sequences. PMID:16808536

Sánchez-Abella, Laura; Fernández, Susana; Armesto, Nuria; Ferrero, Miguel; Gotor, Vicente

2006-07-01

63

A minimal structural analogue of cyclic ADP-ribose: synthesis and calcium release activity in mammalian cells.  

PubMed

Cyclic ADP-ribose (cADPR) is an endogenous Ca(2+)-mobilizing second messenger in many cell types and organisms. Although the biological activity of several modified analogues of cADPR has been analyzed, most of these structures were still very similar to the original molecule. Recently, we have introduced simplified analogues in which the northern ribose (N(1)-linked ribose) was replaced by an ether strand. Here we also demonstrate that the southern ribose (N(9)-linked ribose) can be replaced by an ether strand resulting in N(1)-[(phosphoryl-O-ethoxy)-methyl]-N(9)-[(phosphoryl-O-ethoxy)-methyl]-hypoxanthinecyclic pyrophosphate (cIDP-DE). This minimal structural analogue of cyclic ADP-ribose released Ca(2+) from intracellular stores of permeabilized Jurkat T lymphocytes. In intact T lymphocytes initial subcellular Ca(2+) release events, global Ca(2+) release, and subsequent global Ca(2+) entry were observed. Cardiac myocytes freshly prepared from mice responded to cIDP-DE by increased recruitment of localized Ca(2+) signals and by global Ca(2+) waves. PMID:15713671

Guse, Andreas H; Gu, Xianfeng; Zhang, Liangren; Weber, Karin; Krämer, Elisabeth; Yang, Zhenjun; Jin, Hongwei; Li, Qin; Carrier, Lucie; Zhang, Lihe

2005-04-22

64

Amide-controlled, one-pot synthesis of tri-substituted purines generates structural diversity and analogues with trypanocidal activity.  

PubMed

A novel one-pot synthesis of tri-substituted purines and the discovery of purine analogues with trypanocidal activity are reported. The reaction is initiated by a metal-free oxidative coupling of primary alkoxides and diaminopyrimidines with Schiff base formation and subsequent annulation in the presence of large N,N-dimethylamides (e.g. N,N-dimethylpropanamide or larger). This synthetic route is in competition with a reaction previously-reported by our group, allowing the generation of a combinatorial library of tri-substituted purines by the simple modification of the amide and the alkoxide employed. Among the variety of structures generated, two purine analogues displayed trypanocidal activity against the protozoan parasite Trypanosoma brucei with IC50 < 5??M, being each of those compounds obtained through each of the synthetic pathways. PMID:25773920

Pineda de Las Infantas Y Villatoro, Maria J; Unciti-Broceta, Juan D; Contreras-Montoya, Rafael; Garcia-Salcedo, Jose A; Gallo Mezo, Miguel A; Unciti-Broceta, Asier; Diaz-Mochon, Juan J

2015-01-01

65

Insights into the electronic structure of Cu(II) bound to an imidazole analogue of westiellamide.  

PubMed

Three synthetic analogues of westiallamide, H3L(wa), have previously been synthesized (H3L(1-3)) that have a common backbone (derived from l-valine) with H3L(wa) but differ in their heterocyclic rings (imidazole, oxazole, thiazole, and oxazoline). Herein we explore in detail through high-resolution pulsed electron paramagnetic resonance (EPR) and magnetic circular dichroism (MCD) spectroscopy in conjunction with density functional theory (DFT) the geometric and electronic structures of the mono- and dinuclear Cu(II) complexes of these cyclic pseudo hexapeptides. Orientation-selective hyperfine sublevel correlation, electron nuclear double resonance, and three-pulse electron spin echo envelope modulation spectroscopy of [Cu(II)(H2L(1))(MeOH)2](+) reveal delocalization of the unpaired electron spin onto the ligating and distal nitrogens of the coordinated heterocyclic rings and that they are magnetically inequivalent. DFT calculations confirm this and show similar spin densities on the distal heteroatoms in the heterocyclic rings coordinated to the Cu(II) ion in the other cyclic pseudo hexapeptide [Cu(II)(H2L(2,3,wa))(MeOH)2](+) complexes. The magnetic inequivalencies in [Cu(II)(H2L(1))(MeOH)2](+) arise from different orientations of the heterocyclic rings coordinated to the Cu(II) ion, and the delocalization of the unpaired electron onto the distal heteroatoms within these N-methylimidazole rings depends upon their location with respect to the Cu(II) d(x(2)-y(2)) orbital. A systematic study of DFT functionals and basis sets was undertaken to examine the ability to reproduce the experimentally determined spin Hamiltonian parameters. Inclusion of spin-orbit coupling (SOC) using MAG-ReSpect or ORCA with a BHLYP/IGLO-II Wachters setup with SOC corrections and ?38% Hartree-Fock exchange gave the best predictions of the g and A((63)Cu) matrices. DFT calculations of the (14)N hyperfine and quadrupole parameters for the distal nitrogens of the coordinated heterocyclic rings in [Cu(II)(H2L(1))(MeOH)2](+) with the B1LYP functional and the SVP basis set were in excellent agreement with the experimental data, though other choices of functional and basis set also provided reasonable values. MCD, EPR, mass spectrometry, and DFT showed that preparation of the dinuclear Cu(II) complex in a 1:1 MeOH/glycerol mixture (necessary for MCD) resulted in the exchange of the bridging methoxide ligand for glycerol with a corresponding decrease in the magnitude of the exchange coupling. PMID:25393875

Comba, Peter; Dovalil, Nina; Hanson, Graeme R; Harmer, Jeffrey R; Noble, Christopher J; Riley, Mark J; Seibold, Bjoern

2014-12-01

66

Information Theoretic Secret Key Generation: Structured Codes and Tree Packing  

ERIC Educational Resources Information Center

This dissertation deals with a multiterminal source model for secret key generation by multiple network terminals with prior and privileged access to a set of correlated signals complemented by public discussion among themselves. Emphasis is placed on a characterization of secret key capacity, i.e., the largest rate of an achievable secret key,…

Nitinawarat, Sirin

2010-01-01

67

Bisubstrate analogue structure–activity relationships for p300 histone acetyltransferase inhibitors  

Microsoft Academic Search

p300 and CBP are important histone acetyltransferases (HATs) that regulate gene expression and may be anti-cancer drug targets. Based on a previous lead compound, Lys-CoA, we have used solid phase synthesis to generate a series of 11 new analogues and evaluated these compounds as HAT inhibitors. Increased spacing between the CoA moiety and the lysyl moiety generally decreases inhibitory potency.

Vatsala Sagar; Weiping Zheng; Paul R Thompson; Philip A Cole

2004-01-01

68

Structural Analogues of Smoothened Intracellular Loops as Potent Inhibitors of Hedgehog Pathway and Cancer Cell Growth  

PubMed Central

Smoothened is a critical component of the Hedgehog pathway that is essential for stem cell renewal and is dysregulated in many cancer types. We have found synthetic analogues of the second and third intracellular loops of smoothened to be potent inhibitors of the Hedgehog pathway. Palmitoylated peptides as short as 10 residues inhibited melanoma cells growth with IC50 in the low nanomolar range. The compounds are promising drug candidates and convenient tools for solving mechanisms of Hedgehog signaling. PMID:17685505

Remsberg, Jarrett R.; Lou, Hong; Tarasov, Sergey G.; Dean, Michael; Tarasova, Nadya I.

2014-01-01

69

Structure of a Complex between a Cap Analogue and mRNA Guanylyl Transferase Demonstrates the Structural Chemistry of RNA Capping  

Microsoft Academic Search

Paramecium bursaria Chlorella virus PBCV-1 mRNA guanylyl transferase (capping enzyme) has been complexed with an mRNA cap analogue G[5']ppp[5']G and crystallized. The crystals belong to space group C2221 with unit cell dimensions a = 78.4 angstrom, b = 164.1 angstrom, c = 103.3 angstrom, and diffraction data to 3.1 angstrom has been collected by using synchrotron radiation. The structure has

Kjell Hakansson; Dale B. Wigley

1998-01-01

70

Synthesis and biological evaluation of himanimide C and unnatural analogues.  

PubMed

Recently isolated himanimide C (1) can be prepared via a short, flexible, and stereoselective synthesis using a copper-mediated tandem vicinal difunctionalization of dimethyl acetylenedicarboxylate (DMAD, 8) as a key step. The flexibility of the synthesis is exemplified by the preparation of new unnatural himanimide analogues in order to investigate the fungicidal potency of this new family. [structure: see text] PMID:15704905

Sellès, Patrice

2005-02-17

71

The antibacterial properties of 6-tuliposide B. Synthesis of 6-tuliposide B analogues and structure-activity relationship.  

PubMed

6-Tuliposide B is a secondary metabolite occurring specifically in tulip anthers. Recently, a potent antibacterial activity of 6-tuliposide B has been reported. However, its molecular target has not yet been established, nor its action mechanism. To shed light on such issues, 6-tuliposide B and tulipalin B analogues were synthesized and a structure-activity relationship (SAR) was examined using a broad panel of bacterial strains. As the results of SAR among a total of 25 compounds, only tulipalin B and the compounds having 3',4'-dihydroxy-2'-methylenebutanoate (DHMB) moieties showed any significant antibacterial activity. Moreover, the 3'R analogues of these compounds displayed essentially the same activities as 6-tuliposide B and the structure of the 3'R-DMBA moiety was the same as that of the proposed active moiety of cnicin. These results suggest that 6-tuliposide B has the same action mechanism as proposed for cnicin and bacterial MurA is one of the major molecular targets of 6-tuliposide B. PMID:19939419

Shigetomi, Kengo; Shoji, Kazuaki; Mitsuhashi, Shinya; Ubukata, Makoto

2010-02-01

72

Three-dimensional quantitative structure-activity relationship study on antioxidant capacity of curcumin analogues  

NASA Astrophysics Data System (ADS)

A comparative molecular similarity indices analysis (CoMSIA) was performed on a set of 27 curcumin-like diarylpentanoid analogues with the radical scavenging activities. A significant cross-validated correlation coefficient Q2 (0.784), SEP (0.042) for CoMSIA were obtained, indicating the statistical significance of the correlation. Further we adopt a rational approach toward the selection of substituents at various positions in our scaffold,and finally find the favored and disfavoured regions for the enhanced antioxidative activity. The results have been used as a guide to design compounds that, potentially, have better activity against oxidative damage.

Chen, Bohong; Zhu, Zhibo; Chen, Min; Dong, Wenqi; Li, Zhen

2014-03-01

73

Analysis of structural requirements for TRH-potentiating peptide receptor binding by analogue design.  

PubMed

Previous studies established that the [125I-Tyr0]Ps4 derivative of TRH-potentiating peptide (Ps4), Ser-Phe-Pro-Trp-Met-Glu-Ser-Asp-Val-Thr, displays high affinity and selectivity for an orphan membrane receptor in rat anterior pituitary. To identify the sites in Ps4 that determine receptor binding affinity, we have synthesized and screened a panel of 15 single-point substituted analogues for their ability to displace bound [125I-Tyr0]Ps4. The affinity of [Tyr0]Ps4 for rat anterior pituitary membranes [inhibitory constant (Ki), approximately 5 nM] was drastically reduced by the substitution of either Tyr0 with Gly or Asp8 with Asn (Ki approximately 95 and approximately 51 nM, respectively). Deamination of [Tyr0]Ps4 also sharply reduced affinity (Ki approximately 1100 nM). In contrast, Ser1-->Ala, Pro3-->Ala and Thr10-->Val substitutions led to analogues showing a tenfold increase in binding affinity relative to the parent peptide. The change of Phe2-->Leu, Trp4-->Ala, Glu6-->Gln, Val9-->Thr and carboxamidation of Thr10 had no effect on binding affinity. The data suggest that substitutions of the amino-terminal group, Asp8 and Tyr0, have a marked effect on the ability of [Tyr0]Ps4 to compete with [125I-Tyr0]Ps4 for binding to TRH-potentiating peptide pituitary receptor. PMID:7937314

Ladram, A; Montagne, J J; Bulant, M; Nicolas, P

1994-01-01

74

Binding of bilirubin and its structural analogues to hepatic microsomal bilirubin UDP glucuronyltransferase  

SciTech Connect

Hepatic glucuronidation of the asymmetrical natural bilirubin molecule results in formation of two different positional isomers, bilirubin C-8 monoglucuronide and bilirubin C-12 monoglucuronide. In view of the existence of multiple isoforms of UDPglucuronyltransferase, which is the microsomal enzyme system responsible for bilirubin esterification, the authors performed kinetic analysis of microsomal glucuronidation of bilirubin and a number of its structural congeners to determine whether synthesis of the two monoglucuronide isomers involved two distinct substrate-binding sites or reflected two different modes of binding to a single catalytic site. Both isomers were found in all tested species (man, rat, guinea pig, sheep), but there were marked species differences in the C-8/C-12 ratio of monoglucuronide found in bile or formed by liver microsomes. Correspondence between in vivo and in vitro results for such regioselectivity of glucuronidation was excellent in each species. On the basis of these results of kinetic analysis of bilirubin esterification at variable pigment substrate concentrations and inhibition studies with alternative substrates, the authors postulate that both natural monoglucuronide isomers are synthesized at a single binding site. Possible mechanisms responsible for the markedly regioselective esterification of bilirubin by rat and sheep liver were investigated by study of glucuronidation of selected structural analgoues of the pigment. Collectively, their findings suggest that the molecular from(s) of bilirubin able to engage in catalytically effective binding to UDPglucuronyltransferase does (do) not correspond with intramolecularly hydrogen-bonded conformers and that the nature of the ..beta..-substituents of the outer pyrromethenone rings is a key determinant of glucuronidation rate.

Vanstapel, F.; Blanckaert, N.

1987-09-22

75

Structural characteristics of chloroquine-bridged ferrocenophane analogues of ferroquine may obviate malaria drug-resistance mechanisms.  

PubMed

Five compounds displaying an unprecedented binding mode of chloroquine to ferrocene through the bridging of the cyclopentadienyl rings were studied alongside their monosubstituted ferrocene analogues and organic fragments. The antiplasmodial activity was evaluated against strains of the malaria parasite (Plasmodium falciparum). While the chloroquine-bridged ferrocenyl derivatives were less active than their five monosubstituted ferrocenyl analogues, they retained activity in the drug-resistant strains. The biological and physical properties were correlated to antiplasmodial activity. Intramolecular hydrogen bonding was associated with increased antiplasmodial action, but it is not the determining factor. Instead, balance between lipophilicity and hydrophilicity had a greater influence. It was found that calculated partition coefficient (log P) values of 4.5-5.0 and topological polar surfaces area (tPSA) values of ?26.0 Å(2) give the best balance. The particular conformation, compact size, and lipophilicity/hydrophilicity balance observed in the bridged compounds provide them with the structural characteristics needed to escape the mechanisms responsible for resistance. PMID:23327489

Salas, Paloma F; Herrmann, Christoph; Cawthray, Jacqueline F; Nimphius, Corinna; Kenkel, Alexander; Chen, Jessie; de Kock, Carmen; Smith, Peter J; Patrick, Brian O; Adam, Michael J; Orvig, Chris

2013-02-28

76

Novel dinucleoside 5',5'-triphosphate cap analogues. Synthesis and affinity for murine translation factor eIF4E.  

PubMed

Chemical synthesis of a series of novel dinucleoside cap analogues, m7GpppN, where N is formycin A, 3'-O-methylguanosine, 9-beta-D-arabinofuranosyladenine, and isoguanosine, has been performed using our new methodology. The key reactions of pyrophosphate bonds formation were achieved in anhydrous dimethylformamide solutions employing the catalytic properties of zinc salts. Structures of the new cap analogues were confirmed by 1H NMR and 31p NMR spectra. The binding affinity of the new cap analogues for murine eIF4E(28-217) were determined spectroscopically showing the highest association constant for the analogue that contains formycin A. PMID:16248001

Stepinski, Janusz; Zuberek, Joanna; Jemielity, Jacek; Kalek, Marcin; Stolarski, Ryszard; Darzynkiewicz, Edward

2005-01-01

77

Characterizing, identifying and mapping structural domains at rifted continental margins: insights from the Bay of Biscay margins and its Pyrenean fossil analogue  

NASA Astrophysics Data System (ADS)

The occurrence of hyperextended domains at rifted continental margins consisting of extremely thinned crust and/or exhumed mantle has been increasingly recognized over the past decades, both at present-day rifted margins and in deformed remnants preserved in collisional orogens. At present, most studies aiming to characterize rifted continental margin structure and the extreme thinning of the continental crust and lithosphere are either focused offshore using geophysical methods, or onshore on fossil analogues relying on geological field observations. Marine and onland examples provide complementary datasets, but their different scale and resolution of observations prevent straightforward correlations to be done. In this contribution, we use the Bay of Biscay and Western Pyrenees to develop and apply a geological/geophysical approach to characterize and identify distinctive rifted margin domains both in offshore and onshore settings. The Bay of Biscay and Western Pyrenees represent a unique natural laboratory that offer the possibility to have access to seismically imaged, drilled and exposed parts of one and the same hyperextended rift system. Quantitative techniques (gravity inversion and flexural backstripping) are used on offshore examples (Western Approach margin and Parentis basin) to estimate accommodation space, crustal thickness and lithosphere thinning while seismic interpretations enable the recognition of extensional settings (low- and high-? settings). Field observations (Mauléon basin) and drill-hole data (Parentis basin) focused on key outcrops enables the description of the nature of sediment and basement rocks and of the structures forming fossil remnants of rifted margins. This qualitative and quantitative characterisation provides diagnostic elements to identify and map structural domains at magma-poor rifted margins and their fossil analogues. We name these 5 domains proximal, necking, hyperthinned, exhumed mantle and oceanic. This new geological/geophysical approach can be further used as an interface between onshore and offshore observations. Offshore seismic interpretations can take advantage of onshore observations on the nature of sediment, basement and of their interface. The large scale geometry and stratigraphic architecture imaged offshore can be used to restore onshore fossil remnants back into a rifted margin context. The application of this multidisciplinary approach to the Bay of Biscay margins and their onshore Pyrenean fossils remnants enables us to propose a new map of the different rift systems preserved at the transition between the European and Iberian plates. The approach underlying this mapping has general global application to unravelling the spatial and temporal complexity of rifted margin structural domains.

Tugend, Julie; Manatschal, Gianreto; Kusznir, Nick J.

2014-05-01

78

Crystal structure and computational investigation of an analogue of Grubbs' second generation catalyst with a fluorous phosphine.  

PubMed

A fluorous phosphine analogue of Grubbs' second generation olefin metathesis catalyst, (H(2)IMes)((R(f8)(CH(2))(2))(3)P)(Cl)(2)Ru(=CHPh) (1; H(2)IMes/R(f8) = 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene/(CF(2))(7)CF(3)) is crystallized and the X-ray structure analyzed in detail. The bond lengths and angles about ruthenium are compared to those of two solvates and five derivatives of Grubbs' second generation catalyst. All exhibit distorted square pyramidal geometries in which the alkylidene ligands occupy apical positions, and geometric trends are interpreted with the help of density functional calculations. The perfluoroalkyl groups (1) exhibit helical conformations, as manifested by various torsional relationships, (2) segregate in the lattice, and (3) align in pairs of opposite helical chiralities. PMID:22954330

Tuba, Robert; Brothers, Edward N; Reibenspies, Joseph H; Bazzi, Hassan S; Gladysz, John A

2012-09-17

79

Structural analyses of covalent enzyme-substrate analogue complexes reveal strengths and limitations of de novo enzyme design  

PubMed Central

We report the cocrystal structures of a computationally designed and experimentally optimized retro-aldol enzyme with covalently bound substrate analogs. The structure with covalently bound substrate analog is similar but not identical to the design model, with an RMSD over the active site residues and equivalent substrate atoms of 1.4Å. As in the design model, the binding pocket orients the substrate through hydrophobic interactions with the naphthyl moiety such that the oxygen atoms analogous to the carbinolamine and ?-hydroxyl oxygens are positioned near a network of bound waters. However, there are differences between the design model and the structure: the orientation of the naphthyl group and the conformation of the catalytic lysine are slightly different; the bound water network appears to be more extensive; and the bound substrate analog exhibits more conformational heterogeneity than in typical native enzyme-inhibitor complexes. Alanine scanning of the active site residues shows that both the catalytic lysine and the residues around the binding pocket for the substrate naphthyl group make critical contributions to catalysis. Mutating the set of water-coordinating residues also significantly reduces catalytic activity. The crystal structure of the enzyme with a smaller substrate analogue that lacks the naphthyl rings shows the catalytic lysine to be more flexible than in the naphthyl substrate complex; increased preorganization of the active site would likely improve catalysis. The covalently bound complex structures and mutagenesis data highlight strengths and weaknesses of the de novo enzyme design strategy. PMID:22075445

Wang, Ling; Althoff, Eric A.; Bolduc, Jill; Jiang, Lin; Moody, James; Lassila, Jonathan K.; Giger, Lars; Hilvert, Donald; Stoddard, Barry; Baker, David

2012-01-01

80

Kinetic, thermodynamic and X-ray structural insights into the interaction of melatonin and analogues with quinone reductase 2  

SciTech Connect

Melatonin exerts its biological effects through at least two transmembrane G-protein-coupled receptors, MT1 and MT2, and a lower-affinity cytosolic binding site, designated MT3. MT3 has recently been identified as QR2 (quinone reductase 2) (EC 1.10.99.2) which is of significance since it links the antioxidant effects of melatonin to a mechanism of action. Initially, QR2 was believed to function analogously to QR1 in protecting cells from highly reactive quinones. However, recent studies indicate that QR2 may actually transform certain quinone substrates into more highly reactive compounds capable of causing cellular damage. Therefore it is hypothesized that inhibition of QR2 in certain cases may lead to protection of cells against these highly reactive species. Since melatonin is known to inhibit QR2 activity, but its binding site and mode of inhibition are not known, we determined the mechanism of inhibition of QR2 by melatonin and a series of melatonin and 5-hydroxytryptamine (serotonin) analogues, and we determined the X-ray structures of melatonin and 2-iodomelatonin in complex with QR2 to between 1.5 and 1.8 {angstrom} (1 {angstrom} = 0.1 nm) resolution. Finally, the thermodynamic binding constants for melatonin and 2-iodomelatonin were determined by ITC (isothermal titration calorimetry). The kinetic results indicate that melatonin is a competitive inhibitor against N-methyldihydronicotinamide (K{sub i} = 7.2 {mu}M) and uncompetitive against menadione (K{sub i} = 92 {mu}M), and the X-ray structures shows that melatonin binds in multiple orientations within the active sites of the QR2 dimer as opposed to an allosteric site. These results provide new insights into the binding mechanisms of melatonin and analogues to QR2.

Calamini, Barbara; Santarsiero, Bernard D.; Boutin, Jean A.; Mesecar, Andrew D. (IdRS); (UIC)

2008-09-12

81

Preparation and crystal structure of a rhenium analogue of the cationic renal agent, tc-99m diaminocyclohexane.  

PubMed

We report here a chemical study on a Re analogue of one of the few cationic Tc-99m tracers previously investigated as an agent for effective renal plasma flow (ERPF) measurement. Cationic Tc-99m tracers have the potential for overcoming problems associated with common anionic Tc-99m tracers in patients who have developed a uremic state. The Tc-99m-DACH tracer, prepared from 1,2-diaminocyclohexane (1,2-DACH), is the only cationic renal agent tested in humans and has seven possible isomers. The complex isolated from the reaction of the racemic mixture, (+/-)-trans-1,2-DACH, and ReIO(2)(PPh(3))(2) after conversion to the BPh(4) (-) salt was found by X-ray crystallography to be the meso isomer, trans-[ReO(2) (trans-R,R-1,2-DACH)(trans-S,S-l,2-DACH)][BPh(4)].MeOH.2H(2)O (1). The structural parameters for 1 are normal. The complex is highly symmetrical, suggesting that the analogous meso Tc-99m-DACH agent is also symmetrical. Studies of other Tc-99m-DACH agents that were made from cis-1,2-DACH or individual trans-1,2-DACH enantiomers show that the biodistribution is not very dependent on the starting 1,2-DACH ligand stereochemistry; these agents must be less symmetrical than the meso Tc-99m-DACH agent analogue of 1. Thus, the overall charge and lipophilicity (similar for all Tc-99m-DACH isomers) exert a greater influence on biodistribution than the specific structural features of the different Tc-99m-DACH isomers. PMID:18475937

Marzilli, L G; Hansen, L; Taylor, A; Lachicotte, R

2000-01-01

82

Preparation and Crystal Structure of a Rhenium Analogue of the Cationic Renal Agent, Tc-99m Diaminocyclohexane  

PubMed Central

We report here a chemical study on a Re analogue of one of the few cationic Tc-99m tracers previously investigated as an agent for effective renal plasma flow (ERPF) measurement. Cationic Tc-99m tracers have the potential for overcoming problems associated with common anionic Tc-99m tracers in patients who have developed a uremic state. The Tc-99m-DACH tracer, prepared from 1,2-diaminocyclohexane (1,2-DACH), is the only cationic renal agent tested in humans and has seven possible isomers. The complex isolated from the reaction of the racemic mixture, (±)-trans-1,2-DACH, and ReIO2(PPh3)2 after conversion to the BPh4- salt was found by X-ray crystallography to be the meso isomer, trans-[ReO2 (trans-R,R-1,2-DACH)(trans-S,S-l,2-DACH)][BPh4]·MeOH·2H2O (1). The structural parameters for 1 are normal. The complex is highly symmetrical, suggesting that the analogous meso Tc-99m-DACH agent is also symmetrical. Studies of other Tc-99m-DACH agents that were made from cis-1,2-DACH or individual trans-1,2-DACH enantiomers show that the biodistribution is not very dependent on the starting 1,2-DACH ligand stereochemistry; these agents must be less symmetrical than the meso Tc-99m-DACH agent analogue of 1. Thus, the overall charge and lipophilicity (similar for all Tc-99m-DACH isomers) exert a greater influence on biodistribution than the specific structural features of the different Tc-99m-DACH isomers. PMID:18475937

Hansen, Lory; Taylor, Andrew; Lachicotte, Rene

2000-01-01

83

Structure-activity relationship study of permethyl ningalin B analogues as P-glycoprotein chemosensitizers.  

PubMed

A novel series of permethyl ningalin B analogues were synthesized and evaluated for their P-glycoprotein (P-gp)-modulating activities in a P-gp-overexpressing breast cancer cell line (LCC6MDR). Compounds 35 and 37, which possess one methoxy group and one benzyloxy group at aryl ring C, displayed the most potent P-gp-modulating activity. A 1 ?M concentration of 35 and 37 resensitized LCC6MDR cells toward paclitaxel by 42.7-fold, with respective EC50 values of 93.5 and 110.0 nM. Their mechanism of P-gp modulation is associated with an increase in intracellular drug accumulation. Their advantages also include low cytotoxicity (IC50 for L929 fibroblast >100 ?M) and high therapeutic indexes (>909 after normalization with their EC50 values). 35 is not a substrate of P-gp. They are potentially dual-selective modulators for both P-gp and breast cancer resistance protein transporters. The present study demonstrates that these new compounds can be employed as effective and safe modulators of P-gp-mediated drug resistance in cancer cells. PMID:24171478

Bin, Jin Wen; Wong, Iris L K; Hu, Xuesen; Yu, Zhang Xiao; Xing, Li Fu; Jiang, Tao; Chow, Larry M C; Biao, Wan Sheng

2013-11-27

84

CONSIDERATION OF REACTION INTERMEDIATES IN STRUCTURE-ACTIVITY RELATIONSHIPS: A KEY TO UNDERSTANDING AND PREDICTION  

EPA Science Inventory

Consideration of Reaction Intermediates in Structure- Activity Relationships: A Key to Understanding and Prediction A structure-activity relationship (SAR) represents an empirical means for generalizing chemical information relative to biological activity, and is frequent...

85

Non-natural acetogenin analogues as potent Trypanosoma brucei inhibitors  

PubMed Central

A series of novel bis-tetrahydropyran 1,4-triazole analogues based on the acetogenin framework display low micromolar trypanocidal activities towards both bloodstream and insect forms of Trypanosoma brucei, the causative agent of African sleeping sickness. A divergent synthetic strategy was adopted for the synthesis of the key tetrahydropyran intermediates to enable rapid access to diastereochemical variation either side of the 1,4-triazole core. The resulting diastereomeric analogues displayed varying degrees of trypanocidal activity and selectivity in structure activity relationship studies. PMID:25145275

Florence, Gordon J.; Fraser, Andrew L.; Gould, Eoin R.; King, Elizabeth F.; Menzies, Stefanie K.; Morris, Joanne C.; Tulloch, Lindsay B.; Smith, Terry K.

2015-01-01

86

The structures of thymidine kinase from herpes simplex virus type 1 in complex with substrates and a substrate analogue.  

PubMed Central

Thymidine kinase from Herpes simplex virus type 1 (TK) was crystallized in an N-terminally truncated but fully active form. The structures of TK complexed with ADP at the ATP-site and deoxythymidine-5'-monophosphate (dTMP), deoxythymidine (dT), or idoxuridine-5'-phosphate (5-iodo-dUMP) at the substrate-site were refined to 2.75 A, 2.8 A, and 3.0 A resolution, respectively. TK catalyzes the phosphorylation of dT resulting in an ester, and the phosphorylation of dTMP giving rise to an anhydride. The presented TK structures indicate that there are only small differences between these two modes of action. Glu83 serves as a general base in the ester reaction. Arg163 parks at an internal aspartate during ester formation and binds the alpha-phosphate of dTMP during anhydride formation. The bound deoxythymidine leaves a 35 A3 cavity at position 5 of the base and two sequestered water molecules at position 2. Cavity and water molecules reduce the substrate specificity to such an extent that TK can phosphorylate various substrate analogues useful in pharmaceutical applications. TK is structurally homologous to the well-known nucleoside monophosphate kinases but contains large additional peptide segments. PMID:9336833

Wild, K.; Bohner, T.; Folkers, G.; Schulz, G. E.

1997-01-01

87

Consequences of binding an S-adenosylmethionine analogue on the structure and dynamics of the thiopurine methyltransferase protein backbone.  

PubMed

In humans, the enzyme thiopurine methyltransferase (TPMT) metabolizes 6-thiopurine (6-TP) medications, commonly used for immune suppression and for the treatment of hematopoietic malignancies. Genetic polymorphisms in the TPMT protein sequence accelerate intracellular degradation of the enzyme through an ubiquitylation and proteasomal-dependent pathway. Research has led to the hypothesis that these polymorphisms destabilize the native structure of TPMT, resulting in the formation of misfolded or partially unfolded states, which are subsequently recognized for intracellular degradation. Addition of the cosubstrate, S-adenosylmethionine (SAM), prevents degradation of the TPMT polymorphs in experimental assays, presumably by stabilizing the native structure. Using a bacterial orthologue of TPMT from Pseudomonas syringae, we have used NMR spectroscopy to describe the consequences of binding sinefungin, a SAM analogue, on the structure and dynamics of the TPMT protein backbone. NMR chemical shift mapping experiments localize sinefungin to a highly conserved site in classical methyltransferases. Distal chemical shift changes involving the presumed active site cover imply indirect conformational changes induced by sinefungin, which may play a role in substrate recognition or the catalytic mechanism. Analysis of protein backbone dynamics based on NMR relaxation reveals a combination of complementary effects. Whereas the peripheral, inserted structural elements of the TPMT topology are conformationally stabilized by the presence of sinefungin, a consistent increase in backbone mobility is observed for the central, conserved structural elements. The potential implications for the structural and dynamic effects of binding sinefungin for the catalytic mechanism of the enzyme and the stabilization of the degradation-susceptible TPMT polymorphs are discussed. PMID:15379558

Scheuermann, Thomas H; Keeler, Camille; Hodsdon, Michael E

2004-09-28

88

Structural visualization of key steps in human transcription initiation.  

PubMed

Eukaryotic transcription initiation requires the assembly of general transcription factors into a pre-initiation complex that ensures the accurate loading of RNA polymerase II (Pol II) at the transcription start site. The molecular mechanism and function of this assembly have remained elusive due to lack of structural information. Here we have used an in vitro reconstituted system to study the stepwise assembly of human TBP, TFIIA, TFIIB, Pol II, TFIIF, TFIIE and TFIIH onto promoter DNA using cryo-electron microscopy. Our structural analyses provide pseudo-atomic models at various stages of transcription initiation that illuminate critical molecular interactions, including how TFIIF engages Pol II and promoter DNA to stabilize both the closed pre-initiation complex and the open-promoter complex, and to regulate start--initiation complexes, combined with the localization of the TFIIH helicases XPD and XPB, support a DNA translocation model of XPB and explain its essential role in promoter opening. PMID:23446344

He, Yuan; Fang, Jie; Taatjes, Dylan J; Nogales, Eva

2013-03-28

89

Analysis of Wave Propagation in Stratified Structures Using Circuit Analogues, with Application to Electromagnetic Absorbers  

ERIC Educational Resources Information Center

This paper presents an overview of how circuit models can be used for analysing wave propagation in stratified structures. Relatively complex structures can be analysed using models which are accessible to undergraduate students. Homogeneous slabs are modelled as transmission lines, and thin sheets between the slabs are modelled as lumped…

Sjoberg, Daniel

2008-01-01

90

Functional and Structural Analysis of a Key Region of the Cell Wall Inhibitor Moenomycin  

SciTech Connect

Moenomycin A (MmA) belongs to a family of natural products that inhibit peptidoglycan biosynthesis by binding to the peptidoglycan glycosyltransferases, the enzymes that make the glycan chains of peptidoglycan. MmA is remarkably potent, but its clinical utility has been hampered by poor physicochemical properties. Moenomycin contains three structurally distinct regions: a pentasaccharide, a phosphoglycerate, and a C25 isoprenyl (moenocinyl) lipid tail that gives the molecule its name. The phosphoglycerate moiety links the pentasaccharide to the moenocinyl chain. This moiety contains two negatively charged groups, a phosphoryl group and a carboxylate. Both the phosphoryl group and the carboxylate have previously been implicated in target binding but the role of the carboxylate has not been explored in detail. Here we report the synthesis of six MmA analogues designed to probe the importance of the phosphoglycerate. These analogues were evaluated for antibacterial and enzyme inhibitory activity; the specific contacts between the phosphoglycerate and the protein target were assessed by X-ray crystallography in conjunction with molecular modeling. Both the phosphoryl group and the carboxylate of the phosphoglycerate chain play roles in target binding. The negative charge of the carboxylate, and not its specific structure, appears to be the critical feature in binding since replacing it with a negatively charged acylsulfonamide group produces a more active compound than replacing it with the isosteric amide. Analysis of the ligand-protein contacts suggests that the carboxylate makes a critical contact with an invariant lysine in the active site. The reported work provides information and validated computational methods critical for the design of analogues based on moenomycin scaffolds.

Fuse, Shinichiro; Tsukamoto, Hirokazu; Yuan, Yanqiu; Wang, Tsung-Shing Andrew; Zhang, Yi; Bolla, Megan; Walker, Suzanne; Sliz, Piotr; Kahne, Daniel (Harvard-Med); (Harvard)

2010-09-03

91

Structure of 1-aminocyclopropane-1-carboxylate synthase in complex with an amino-oxy analogue of the substrate: implications for substrate binding.  

PubMed

The crystal structure of 1-aminocyclopropane-1-carboxylate (ACC) synthase in complex with the substrate analogue [2-(amino-oxy)ethyl](5'-deoxyadenosin-5'-yl)(methyl)sulfonium (AMA) was determined at 2.01-A resolution. The crystallographic results show that a covalent adduct (oxime) is formed between AMA (an amino-oxy analogue of the natural substrate S-adenosyl-L-methionine (SAM)) and the pyridoxal 5'-phosphate (PLP) cofactor of ACC synthase. The oxime formation is supported by spectroscopic data. The ACC synthase-AMA structure provides reliable and detailed information on the binding mode of the natural substrate of ACC synthase and complements previous structural and functional work on this enzyme. PMID:12686108

Capitani, Guido; Eliot, Andrew C; Gut, Heinz; Khomutov, Radii M; Kirsch, Jack F; Grütter, Markus G

2003-04-11

92

Structural Analysis of Silanediols as Transition-State-Analogue Inhibitors of the Benchmark Metalloprotease Thermolysin,  

E-print Network

). Ketones (hydrated as in 5) have been found to be useful metalloprotease inhibitors (12), and the strong of silanediols is predicated on its resemblance to the hydrated carbonyl transition-state structure of amide hydrated carbonyl 2, employing a central silicon atom, the element most similar to carbon. Silanediol

Juers, Doug

93

Structural characterisation of the natural membrane-bound state of melittin: a fluorescence study of a dansylated analogue.  

PubMed

The binding of a dansylated analogue of melittin (DNC-melittin) to natural membranes is described. The cytolytic peptide from honey bee venom melittin was enzymatically labelled in its glutamine-25 with the fluorescent probe monodansylcadaverine using guinea pig liver transglutaminase. The labelled peptide was characterised functionally in cytolytic assays, and spectroscopically by circular dichroism and fluorescence. The behaviour of DNC-melittin was, in all respects, indistinguishable from that of the naturally occurring peptide. We used resonance energy transfer to measure the state of aggregation of melittin on the membrane plane in synthetic and natural lipid bilayers. When bound to erythrocyte ghost membranes, the extent of energy transfer was found to be equivalent to when bound to small unilamellar vesicles of phosphatidylcholine. Our results correlate best with a proposed model in which the initial interaction between melittin and the red blood cells could be merely electrostatic and the peptide remains in a low alpha-helical conformation. The next step would be a peptide stabilisation in the membrane in a monomeric alpha-helical conformation that would imply the collapse of the membrane structure and liberation of the cell contents. PMID:9371414

Pérez-Payá, E; Dufourcq, J; Braco, L; Abad, C

1997-10-23

94

Structure-toxicity relationship study of para-halogenated styrene analogues in CYP2E1 transgenic cells  

PubMed Central

Styrene is one of the most important industrial intermediates consumed in the world and is mainly used as a monomer for reinforced plastics and rubber. Styrene has been found to be hepatotoxic and pneumotoxic in humans and experimental animals. The toxicity of styrene is suggested to be metabolism-dependent. Styrene-7,8-oxide has been considered as the major metabolite responsible for styrene-induced cytotoxicity. The objective of the study was to investigate the correlation between cytotoxicity of styrene and chemical and biochemical properties of the vinyl group of styrene by development of structure activity relationships (SAR). 4-Fluorostyrene, 4-chlorostyrene and 4-bromostyrene were selected for the SAR study. Cytotoxicity of styrene and the halogenated styrene derivatives with an order of 4-bromostyrene > 4-chlorostyrene > 4-fluorostyrene ? styrene was observed in CYP2E1 transgenic cells. Similar orders in the efficiency of the metabolism of styrene and the halogenated styrene analogues to their oxides and in the electrophilicity of the corresponding oxides were observed. Additionally, the order of the potency of cellular glutathione depletion and the degree of protein adduction induced by styrene and the halogenated styrenes were consistent with that of their cytotoxicities. The wild-type cells were less susceptible to the toxicity of the corresponding model compounds than CYP2E1 cells. The present study provided insight into the roles of the biochemical and chemical properties of styrene in its cytotoxicity. PMID:22366341

Chung, Jou-Ku; Shen, Shuijie; Jiang, Zhiteng; Yuan, Wei; Zheng, Jiang

2012-01-01

95

The influence of cooling on the advance of lava flows: insights from analogue experiments on the feedbacks between flow dynamics and thermal structure  

NASA Astrophysics Data System (ADS)

During an effusive volcanic eruption, the crisis management is mainly based on the prediction of lava flows advance and its velocity. The spreading of a lava flow, seen as a gravity current, depends on its "effective rheology" and the eruptive mass flux. These two parameters are not known a priori during an eruption and a key question is how to evaluate them in near real-time (rather than afterwards.) There is no generic macroscopic model for the rheology of an advancing lava flow, and analogue modelling is a precious tool to empirically estimate the rheology of a complex flow. We investigate through laboratory experiments the simultaneous spreading and cooling of horizontal currents fed at constant rate from a point source. The materials used are silicone oil (isoviscous), and poly-ethylene glycol (PEG) wax injected in liquid state and solidiying during its advance. In the isoviscous case, the temperature field is a passive tracer of the flow dynamics, whereas in the PEG experiments there is a feedback between the cooling of the flow and its effective rheology. We focus on the evolution of the current area and of the surface thermal structure, imaged with an infrared camera, to assess how the thermal structure can be related to the flow rate. The flow advance is continuous in the viscous case, and follows the predictions of Huppert (1982); in that case the surface temperature become steady after a transient time and the radiated heat flux is shown to be proportional to the input rate. For the PEG experiments, the spreading occurs through an alternation of stagnation and overflow phases, with a mean spreading rate decreasing as the experiment goes on. As in the case of lava flows, these experiments can exhibit a compound flow field, solid levees, thermal erosion, liquid overflows and channelization. A key observation is that the effective rheology of the solifying PEG material depends on the input flow rate, with high input rates yielding a rheology closer to the one of an isoviscous fluid. The radiated heat flux evolves by stages, and includes two contributions : the one from "active" flowing part of the flow, and the one from non-moving cooling regions. The "active" thermal signal of the liquid PEG becomes steady as in the isoviscous case. Experimental results show that flow modelling, used to predict lava flow advance or to build hazard maps, should consider the variation of lava rheology as a function of the effusion rate.The experiments show also that dense time series of radiance signals, with high temporal and spectral resolution, are necessary to discriminate active and inactive lava fields, and to interpret the remote-sensed thermal signal in terms of dynamics of lava flows.

Garel, F.; Kaminski, E.; Tait, S.; Limare, A.

2012-12-01

96

Structural studies of "aggregation-prone" peptide-analogues of teleostean egg chorion ZPB proteins.  

PubMed

Egg envelopes of vertebrates are composed of a family of proteins called zona pellucida (ZP) proteins, which are distinguished by the presence of a common structural polymerizing motif, known as ZP domain. Teleostean fish chorion is a fibrous structure, consisting of protein members of the ZPB/ZP1 and the ZPC/ZP3 families, which are incorporated as tandemly repeating heterodimers inside chorion fibers. Computational analysis of multiple ZPB/ZP1 proteins from several teleostean species, reveals two potential "aggregation-prone" sequence segments, forming a specific polymerization interface (AG interface). These two peptides were synthesized and results are presented in this work from transmission electron microscopy, Congo red staining, X-ray fiber diffraction and ATR FT-IR, which clearly display the ability of these peptides to self-aggregate, forming amyloid-like fibrils. This, most probably implies that the AG interface of ZPB/ZP1 proteins plays an important role for the formation of the repeating ZPB-ZPC heterodimers, which constitute teleostean chorion fibrils. © 2014 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 102: 427-436, 2014. PMID:25229478

Louros, Nikolaos N; Petronikolou, Nektaria; Karamanos, Theodoros; Cordopatis, Paul; Iconomidou, Vassiliki A; Hamodrakas, Stavros J

2014-11-01

97

Structural investigation of Np2Co17 and analogue compounds under pressure  

NASA Astrophysics Data System (ADS)

The structural behavior of Np2Co17 is investigated by means of high-pressure diamond-anvil compression measurements and is compared with that of the isostructural compounds Lu2Co17 and Lu2Ni17. The Th2Ni17-type hexagonal crystal structure is preserved with no measurable discontinuous volume collapses up to the highest achieved pressure, p=43 GPa. For Np2Co17, fits to the Birch-Murnaghan and Vinet equations of state give values of the isothermal bulk modulus and its pressure derivative of B0=286 GPa and B0'=3, revealing that this Np compound is a highly incompressible solid with stiffness comparable to that of superhard covalently bonded materials. For the Lu2T17 (T = Co, Ni) compounds, the measured bulk modulus changes from B0=137 GPa for T = Co to B0=257 GPa for T = Ni. The isothermal equation of state for the studied compounds are in excellent agreement with the results of ab initio fully relativistic, full-potential local spin-density functional calculations. Theoretical estimates of the bulk modulus are given also for Np2Ni17, for which B0 is predicted to assume values intermediate between those measured for Lu2Ni17 and Np2Co17.

Hen, A.; Heathman, S.; Eloirdi, R.; Griveau, J.-C.; Elgazzar, S.; Oppeneer, P. M.; Halevy, I.; Orion, I.; Caciuffo, R.

2014-08-01

98

Inhibition and Structure of Trichomonas vaginalis Purine Nucleoside Phosphorylase with Picomolar Transition State Analogues  

SciTech Connect

Trichomonas vaginalis is a parasitic protozoan purine auxotroph possessing a unique purine salvage pathway consisting of a bacterial type purine nucleoside phosphorylase (PNP) and a purine nucleoside kinase. Thus, T. vaginalis PNP (TvPNP) functions in the reverse direction relative to the PNPs in other organisms. Immucillin-A (ImmA) and DADMe-Immucillin-A (DADMe-ImmA) are transition stte mimics of adenosine with geometric and electrostatic features that resemble early and late transition states of adenosine at the transition state stabilized by TvPNP. ImmA demonstrates slow-onset tight-binding inhibition with TvPNP, to give an equilibrium dissociation constant of 87 pM, an inhibitor release half-time of 17.2 min, and a K{sub m}/K{sub d} ratio of 70,100. DADMe-ImmA resembles a late ribooxacarbenium ion transition state for TvPNP to give a dissociation constant of 30 pM, an inhibitor release half-time of 64 min, and a K{sub m}/K{sub d} ratio of 203,300. The tight binding of DADMe-ImmA supports a late S{sub N}1 transition state. Despite their tight binding to TvPNP, ImmA and DADMe-ImmA are weak inhibitors of human and P. falciparum PNPs. The crystal structures of the TvPNP-ImmA{center_dot}PO{sub 4} and TvPNP{center_dot}DADMe-ImmA{center_dot}PO{sub 4} ternary complexes differ from previous structures with substrate anologues. The tight binding with DADMe-ImmA is in part due to a 2.7 {angstrom} ionic interaction between a PO{sub 4} oxygen and the N1 cation of the hydroxypyrrolidine and is weaker in the TvPNP{center_dot}ImmA{center_dot}PO{sub 4} structure at 3.5 {angstrom}. However, the TvPNP{center_dot}ImmA{center_dot}PO{sub 4} structure includes hydrogen bonds between the 2'-hydroxyl and the protein that are not present in TvPNP{center_dot}DADMe-ImmA{center_dot}PO{sub 4}. These structures explain why DADMe-ImmA binds tighter than ImmA. Immucillin-H is a 12 nM inhibitor of TvPNP but a 56 pM inhibitor of human PNP. And this difference is explained by isotope-edited difference infrared spectroscopy with [6-{sup 18}O]ImmH to establish that O6 is the keto tautomer in TvPNP{center_dot}ImmH{center_dot}PO{sub 4}, causing an unfavorable leaving-group interaction.

Rinaldo-Matthis,A.; Wing, C.; Ghanem, M.; Deng, H.; Wu, P.; Gupta, A.; Tyler, P.; Evans, G.; Furneaux, R.; et al.

2007-01-01

99

Structure-activity relationships for the carboxy-terminus truncated analogues of angiotension II, a new class of angiotensin II antagonists.  

PubMed

A series of analogues of the recently reported angiotensin II (AII) antagonist [Sar1]AII-(1-7)-amide or des-Phe8[Sar1]AII (3) have been prepared by solid-phase synthesis and purified by reverse-phase liquid chromatography. The agonist and antagonist properties of these carboxy-truncated analogues of AII were determined in the isolated rabbit aorta assay. In the analogues tested, replacement of aspartic acid in position 1 by sarcosine was found necessary to produce significant antagonist activity. At position 7 of the des-Phe8 analogues, prolinamide could be replaced by proline without significant change in the biological activity. However, substitution of 7-prolinamide by either glycinamide or sarcosinamide provided inactive peptides. Methylation of the 4-tyrosine in [Sar1]AII-(1-7)-NH2 preserved the antagonist potency in isolated rabbit aorta. Deletion of the proline at position 7 resulted in inactive hexapeptides, both in the Asp1 and Sar1 series. However synthesis of the N,N-dimethyl amide at the N-terminus afforded hexapeptide [Sar1]AII-(1-6)-N(CH3)2 (10) with a pA2 value of 7.05. All the antagonistic peptides synthesized were fully reversible, competitive antagonists in vitro. These findings indicate that the structural requirements for receptor blockade by these C-truncated analogues are quite stringent with respect to the nature of the amino acid at positions 1 and 6/7. The analogues 2, 3, 7, 10, 11 (saralasin), and 12 (sarmesin) were tested in vivo in the anesthetized rat and were found to inhibit the AII pressor response. In addition, 3 inhibited angiotensin II stimulated aldosterone release from isolated rat adrenal zona glomerulosa cells and had no agonist activity by itself at the doses tested. Interestingly, analogue 3, when injected intracerebroventricularly in conscious rats, failed to antagonize the dipsogenic response to an angiotensin II icv injection and this reflects some heterogeneity in the AII receptor population. Peptide 3 is the first example of an antagonist that discriminates between peripheral and brain receptor subtypes. PMID:2329570

Bovy, P R; O'Neal, J M; Olins, G M; Patton, D R; McMahon, E G; Palomo, M; Koepke, J P; Salles, K S; Trapani, A J; Smits, G J

1990-05-01

100

Synthesis of structural analogues of hexadecylphosphocholine and their antineoplastic, antimicrobial and amoebicidal activity.  

PubMed

Twelve derivatives of hexadecylphosphocholine (miltefosine) were synthesized to determine how the position and length of the alkyl chain within the molecule influence their biological activities. The prepared alkylphosphocholines have the same molecular formula as miltefosine. Activity of the compounds was studied against a spectrum of tumour cells, two species of protozoans, bacteria and yeast. Antitumour efficacy of some alkylphosphocholines measured up on MCF-7, A2780, HUT-78 and THP-1 cell lines was higher than that of miltefosine. The compounds showed antiprotozoal activity against Acanthamoeba lugdunensis and Acanthamoeba quina. Some of them also possess fungicidal activity against Candida albicans equal to miltefosine. No antibacterial activity was observed against Staphylococcus aureus and Escherichia coli. A difference in position of a long hydrocarbon chain within the structure with maximum efficacy was observed for antitumour, antiprotozoal and antifungal activity. PMID:25698517

Timko, Lukáš; Fischer-Fodor, Eva; Garajová, Mária; Mrva, Martin; Chereches, Gabriela; Ondriska, František; Bukovský, Marián; Luká?, Miloš; Karlovská, Janka; Kubincová, Janka; Devínsky, Ferdinand

2015-03-26

101

Partially folded bovine pancreatic trypsin inhibitor analogues attain fully native structures when co-crystallized with S195A rat trypsin.  

PubMed

Crystal structures, at 1.7 A resolution, were solved for complexes between each of two chemically synthesized partially folded analogues of bovine pancreatic trypsin inhibitor (BPTI) with the proteolytically inactive rat trypsin mutant S195A. The BPTI analogue termed [14-38](Abu) retains only the disulfide bond between Cys14 and Cys38, while Cys5, Cys30, Cys51, and Cys55 are replaced by isosteric alpha-amino-n-butyric acid residues. The analogue K26P,A27D[14-38](Abu) contains two further replacements, by statistically favored residues, in the type I beta-turn that has been suggested to be a main site for initiation of BPTI folding. As a control, the structure of the complex between S195A trypsin and wild-type BPTI was also solved. Despite significant differences in the degree of structure detected among these three BPTIs in solution by several biophysical techniques, their tertiary folds once bound to S195A trypsin in a crystalline lattice are essentially superimposable. PMID:18054043

Getun, Irina V; Brown, C Kent; Tulla-Puche, Judit; Ohlendorf, Douglas; Woodward, Clare; Barany, George

2008-01-18

102

Polyamine analogues targeting epigenetic gene regulation  

PubMed Central

Over the past three decades the metabolism and functions of the polyamines have been actively pursued as targets for antineoplastic therapy. Interactions between cationic polyamines and negatively charged nucleic acids play a pivotal role in DNA stabilization and RNA processing that may affect gene expression, translation and protein activity. Our growing understanding of the unique roles that the polyamines play in chromatin regulation, and the discovery of novel proteins homologous with specific regulatory enzymes in polyamine metabolism, have led to our interest in exploring chromatin remodelling enzymes as potential therapeutic targets for specific polyamine analogues. One of our initial efforts focused on utilizing the strong affinity that the polyamines have for chromatin to create a backbone structure, which could be combined with active-site-directed inhibitor moieties of HDACs (histone deacetylases). Specific PAHAs (polyaminohydroxamic acids) and PABAs (polyaminobenzamides) polyamine analogues have demonstrated potent inhibition of the HDACs, re-expression of p21 and significant inhibition of tumour growth. A second means of targeting the chromatin-remodelling enzymes with polyamine analogues was facilitated by the recent identification of flavin-dependent LSD1 (lysine-specific demethylase 1). The existence of this enzyme demonstrated that histone lysine methylation is a dynamic process similar to other histone post-translational modifications. LSD1 specifically catalyses demethylation of mono- and di-methyl Lys4 of histone 3, key positive chromatin marks associated with transcriptional activation. Structural and catalytic similarities between LSD1 and polyamine oxidases facilitated the identification of biguanide, bisguanidine and oligoamine polyamine analogues that are potent inhibitors of LSD1. Cellular inhibition of LSD1 by these unique compounds led to the re-activation of multiple epigenetically silenced genes important in tumorigenesis. The use of these novel polyamine-based HDAC or LSD1 inhibitors represents a highly promising and novel approach to cancer prevention and therapy. PMID:20095972

Huang, Yi; Marton, Laurence J.; Woster, Patrick M.; Casero, Robert A.

2013-01-01

103

The role of pre-existing tectonic structures and magma chamber shape on the geometry of resurgent blocks: Analogue models  

NASA Astrophysics Data System (ADS)

A set of analogue models has been carried out to understand the role of an asymmetric magma chamber on the resurgence-related deformation of a previously deformed crustal sector. The results are then compared with those of similar experiments, previously performed using a symmetric magma chamber. Two lines of experiments were performed to simulate resurgence in an area with a simple graben-like structure and resurgence in a caldera that collapsed within the previously generated graben-like structure. On the basis of commonly accepted scaling laws, we used dry-quartz sand to simulate the brittle behaviour of the crust and Newtonian silicone to simulate the ductile behaviour of the intruding magma. An asymmetric shape of the magma chamber was simulated by moulding the upper surface of the silicone. The resulting empty space was then filled with sand. The results of the asymmetric-resurgence experiments are similar to those obtained with symmetrically shaped silicone. In the sample with a simple graben-like structure, resurgence occurs through the formation of a discrete number of differentially displaced blocks. The most uplifted portion of the deformed depression floor is affected by newly formed, high-angle, inward-dipping reverse ring-faults. The least uplifted portion of the caldera is affected by normal faults with similar orientation, either newly formed or resulting from reactivation of the pre-existing graben faults. This asymmetric block resurgence is also observed in experiments performed with a previous caldera collapse. In this case, the caldera-collapse-related reverse ring-fault is completely erased along the shortened side, and enhances the effect of the extensional faults on the opposite side, so facilitating the intrusion of the silicone. The most uplifted sector, due to an asymmetrically shaped intrusion, is always in correspondence of the thickest overburden. These results suggest that the stress field induced by resurgence is likely dictated by the geometry of the intruding magma body, and the related deformation is partially controlled by pre-existing tectonic and/or volcano-tectonic structures.

Marotta, Enrica; de Vita, Sandro

2014-02-01

104

EspR, a key regulator of Mycobacterium tuberculosis virulence, adopts a unique dimeric structure  

E-print Network

EspR, a key regulator of Mycobacterium tuberculosis virulence, adopts a unique dimeric structureR is a transcriptional regulator that activates the ESX-1 secretion system during Mycobacterium tuberculosis infection Mycobacterium tuberculosis, an intracellular pathogen that ex- erts an enormous toll on global human health, has

Stroud, Robert

105

Cation radii induced structural variation in fluorescent alkaline earth networks constructed from tautomers of a nucleobase analogue.  

PubMed

Nucleobase tautomers and their metal complexes have attracted considerable attention due to their fascinating architectures along with wide applications. In this paper, 4,6-dihydroxypyrimidine (H(2)DHP), an analogue of uracil and thymine, was employed to react with the vital elements of alkaline earth metals in an aqueous solution and lead to the formation of four novel complexes, [Mg(HDHP)(2) (H(2)O)(4)] (1), [Ca(HDHP)(2)(H(2)O)(3)](n)·nH(2)O (2), [Sr(HDHP)(2)(H(2)O)(3)](n)·nH(2)O (3), and [Ba(HDHP)(2)(H(2)O)(2)](n)·nH(2)O (4), which have been characterized by elemental analysis, IR, TG, UV-Vis, PL, powder and single-crystal X-ray diffraction and progressively evolve from zero-dimensional (0D) mononuclear, one-dimensional (1D) zig-zag double chain, two-dimensional (2D) double layer, to a three-dimensional (3D) porous network along with the increase of cation radii. This tendency in dimensionality follows salient crystal engineering principles and can be explained by considering factors such as hard-soft acid-base principles and cation radii. The deprotonated H(2)DHP ligand exhibits four new coordination modes, namely, O-monodentate (complex 1), N,O-chelating (complexes 2 and 3), O,O-bridging (complexes 2 and 3), and ?(1)O:?(2)O-bridging mode (complex 4). Interestingly, the structural investigation indicates that the HDHP(-) monoanion shows three unusual types of tautomers, which are essential for the diagnosis of disease and investigation of medicine. Furthermore, the four complexes exhibit strong blue emission compared to free H(2)DHP ligand at room temperature and may be potential candidates for blue fluorescent biological materials used in organisms. PMID:22635055

Deng, Zhao-Peng; Kang, Wei; Zhu, Zhi-Biao; Huo, Li-Hua; Zhao, Hui; Gao, Shan

2012-07-21

106

Cytotoxic iron chelators: characterization of the structure, solution chemistry and redox activity of ligands and iron complexes of the di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) analogues.  

PubMed

Di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) and a range of its analogues comprise a series of monobasic acids that are capable of binding iron (Fe) as tridentate ( N, N, O) ligands. Recently, we have shown that these chelators are highly cytotoxic, but show selective activity against cancer cells. Particularly interesting was the fact that cytotoxicity of theHPKIH analogues is maintained even after complexation with Fe. To understand the potent anti-tumor activity of these compounds, we have fully characterized their chemical properties. This included examination of the solution chemistry and X-ray crystal structures of both the ligands and Fe complexes from this class and the ability of these complexes to mediate redox reactions. Potentiometric titrations demonstrated that all chelators are present predominantly in their charge-neutral form at physiological pH (7.4), allowing access across biological membranes. Keto-enol tautomerism of the ligands was identified, with the tautomers exhibiting distinctly different protonation constants. Interestingly, the chelators form low-spin (diamagnetic) divalent Fe complexes in solution. The chelators form distorted octahedral complexes with Fe(II), with two tridentate ligands arranged in a meridional fashion. Electrochemistry of the Fe complexes in both aqueous and non-aqueous solutions revealed that the complexes are oxidized to their ferric form at relatively high potentials, but this oxidation is coupled to a rapid reaction with water to form a hydrated (carbinolamine) derivative, leading to irreversible electrochemistry. The Fe complexes of theHPKIH analogues caused marked DNA degradation in the presence of hydrogen peroxide. This observation confirms that Fe complexes from theHPKIH series mediate Fenton chemistry and do not repel DNA. Collectively, studies on the solution chemistry and structure of theseHPKIH analogues indicate that they can bind cellular Fe and enhance its redox activity, resulting in oxidative damage to vital biomolecules. PMID:14564555

Bernhardt, Paul V; Caldwell, Lorraine M; Chaston, Timothy B; Chin, Piao; Richardson, Des R

2003-11-01

107

Analogues of diverse structure are unable to differentiate native melatonin receptors in the chicken retina, sheep pars tuberalis and Xenopus melanophores.  

PubMed Central

1. The pineal hormone melatonin exerts its biological effects through specific, high affinity G-protein coupled receptors. Recently, three melatonin receptor subtypes (Mel1a, Mel1b and Mel1c) have been cloned. Neither the cloned subtypes, nor the native receptors have yet been compared in a detailed pharmacological analysis. 2. The present study examined the structure-activity relationships of a series of 21 melatonin analogues, by comparing their potency on the pigment aggregation response in Xenopus laevis melanophores with their affinity in radioligand binding competition studies in chicken retina and sheep pars tuberalis (PT), two tissues in which melatonin is known to mediate a biological response. 3. All but four of the analogues were full melatonin receptor agonists producing a concentration-related redistribution of pigment granules in cultured Xenopus melanophores. The remaining analogues produced little pigment aggregation at 10 microM. 4. Saturation studies with 2-[125I]-iodomelatonin identified a single binding site in the chicken retina and sheep PT membranes, with a KD of 36.6 +/- 2.8 and 37.3 +/- 4.3 pM, and a maximal number of binding sites (Bmax) of 16.6 +/- 0.5, and 40.1 +/- 1.7 fmol mg-1 protein, respectively. 5. Comparison of the potency/affinity of the analogues for the binding sites gave a highly significant correlation in each case, retina/melanophore, r = 0.97 (P < 0.001, n = 17), PT/melanophore, r = 0.97 (P < 0.001, n = 17) and PT/retina, r = 0.98 (P < 0.001, n = 21). 6. Despite their large range in affinity and structural diversity these melatonin agonists were unable to distinguish between melatonin receptors in the chicken retina, sheep pars tuberalis and Xenopus melanophores. Images Figure 1 PMID:8886424

Pickering, H.; Sword, S.; Vonhoff, S.; Jones, R.; Sugden, D.

1996-01-01

108

Raman spectroscopic characterisations and analytical discrimination between caffeine and demethylated analogues of pharmaceutical relevance  

NASA Astrophysics Data System (ADS)

The FT Raman spectrum of caffeine was analysed along with that of its demethylated analogues, theobromine and theophylline. The similar but not identical structures of these three compounds allowed a more detailed assignment of the Raman bands. Noticeable differences in the Raman spectra of these compounds were apparent and key marker bands have been identified for the spectroscopic identification of these three compounds.

Edwards, H. G. M.; Munshi, T.; Anstis, M.

2005-05-01

109

Structures of ceftazidime and its transition-state analogue in complex with AmpC beta-lactamase: Implications for resistance mutations and inhibitor design  

SciTech Connect

Third-generation cephalosporins are widely used {beta}-lactam antibiotics that resist hydrolysis by {beta}-lactamases. Recently, mutant {beta}-lactamases that rapidly inactivate these drugs have emerged. To investigate why third-generation cephalosporins are relatively stable to wild-type class C {beta}-lactamases and how mutant enzymes might overcome this, the structures of the class C {beta}-lactamase AmpC in complex with the third-generation cephalosporin ceftazidime and with a transition-state analogue of ceftazidime were determined by X-ray crystallography to 2.0 and 2.3 {angstrom} resolution, respectively. Comparison of the acyl-enzyme structures of ceftazidime and loracarbef, a {beta}-lactam substrate, reveals that the conformation of ceftazidime in the active site differs from that of substrates. Comparison of the structures of the acyl-enzyme intermediate and the transition-state analogue suggests that ceftazidime blocks formation of the tetrahedral transition state, explaining why it is an inhibitor of AmpC. Ceftazidime cannot adopt a conformation competent for catalysis due to steric clashes that would occur with conserved residues Val211 and Tyr221. The X-ray crystal structure of the mutant {beta}-lactamase GC1, which has improved activity against third-generation cephalosporins, suggests that a tandem tripeptide insertion in the {Omega} loop, which contains Val211, has caused a shift of this residue and also of Tyr221 that would allow ceftazidime and other third-generation cephalosporins to adopt a more catalytically competent conformation. These structural differences may explain the extended spectrum activity of GC1 against this class of cephalosporins. In addition, the complexed structure of the transition-state analogue inhibitor (K{sub i} 20 nM) with AmpC reveals potential opportunities for further inhibitor design.

Powers, R.A.; Caselli, E.; Focia, P.J.; Prati, F.; Shoichet, B.K.

2010-03-08

110

Transition state structure of 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase from Escherichia coli and its similarity to transition state analogues.  

PubMed

Methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) catalyzes reactions linked to polyamine metabolism, quorum sensing pathways, methylation reactions, and adenine salvage. It is a candidate target for antimicrobial drug design. Kinetic isotope effects (KIEs) were measured on the MTAN-catalyzed hydrolysis of 5'-methylthioadenosine (MTA) to determine the transition state structure. KIEs measured at pH 7.5 were near unity due to the large forward commitment to catalysis. Intrinsic KIEs were expressed by increasing the pH to 8.5. Intrinsic KIEs from MTAs labeled at 1'-(3)H, 1'-(14)C, 2'-(3)H, 4'-(3)H, 5'-(3)H, 9-(15)N, and Me-(3)H(3) were 1.160 +/- 0.004, 1.004 +/- 0.003, 1.044 +/- 0.004, 1.015 +/- 0.002, 1.010 +/- 0.002, 1.018 +/- 0.006, and 1.051 +/- 0.002, respectively. The large 1'-(3)H and small 1'-(14)C KIEs indicate that the Escherichia coli MTAN reaction undergoes a dissociative (D(N)A(N)) (S(N)1) mechanism with little involvement of the leaving group or participation of the attacking nucleophile at the transition state, causing the transition state to have significant ribooxacarbenium ion character. A transition state constrained to match the intrinsic KIEs was located with density functional theory [B3LYP/6-31G(d,p)]. The leaving group (N9) is predicted to be 3.0 A from the anomeric carbon. The small beta-secondary 2'-(3)H KIE of 1.044 corresponds to a modest 3'-endo conformation for ribose and a H1'-C1'-C2'-H2' dihedral angle of 53 degrees at the transition state. Natural bond orbital analysis of the substrate and the transition state suggests that the 4'-(3)H KIE is due to hyperconjugation between the lone pair (n(p)) of O3' and the antibonding (sigma) orbital of the C4'-H4' group, and the methyl-(3)H(3) KIE is due to hyperconjugation between the n(p) of sulfur and the sigma of methyl C-H bonds. Transition state analogues that resemble this transition state structure are powerful inhibitors, and their molecular electrostatic potential maps closely resemble that of the transition state. PMID:16128565

Singh, Vipender; Lee, Jeffrey E; Núñez, Sara; Howell, P Lynne; Schramm, Vern L

2005-09-01

111

Solid-phase synthesis and insights into structure-activity relationships of safinamide analogues as potent and selective inhibitors of type B monoamine oxidase.  

PubMed

Safinamide, (S)-N2-{4-[(3-fluorobenzyl)oxy]benzyl}alaninamide methanesulfonate, which is in phase III clinical trials as an anti-Parkinson drug, and a library of alkanamidic analogues were prepared through an expeditious solid-phase synthesis and evaluated for their monoamine oxidase B (MAO-B) and monoamine oxidase A (MAO-A) inhibitory activity and selectivity. (S)-3-Chlorobenzyloxyalaninamide (8) and (S)-3-chlorobenzyloxyserinamide (13) derivatives proved to be more potent MAO-B inhibitors than safinamide (IC50 = 33 and 43 nM, respectively, vs 98 nM) but with a lower MAO-B selectivity (SI = 3455 and 1967, respectively, vs 5918). The highest MAO-B inhibitory potency (IC50 = 17 nM) and a good selectivity (SI = 2941) were displayed by (R)-21, a tetrahydroisoquinoline analogue of safinamide. Structure-affinity relationships and docking simulations pointed out strong negative steric effects of alpha-aminoamide side chains and para substituents of the benzyloxy groups and favorable hydrophobic interactions of meta substituents. The significantly diverse MAO-B affinities of a number of R and S alpha-aminoamide enantiomers, including the two rigid analogues (21) of safinamide, indicated likely enantioselective interactions at the enzymatic binding sites. PMID:17824599

Leonetti, Francesco; Capaldi, Carmelida; Pisani, Leonardo; Nicolotti, Orazio; Muncipinto, Giovanni; Stefanachi, Angela; Cellamare, Saverio; Caccia, Carla; Carotti, Angelo

2007-10-01

112

Antimicrobial activities of active component isolated from Lawsonia inermis leaves and structure-activity relationships of its analogues against food-borne bacteria.  

PubMed

The antimicrobial activities of Lawsonia inermis leaf extract and 2-hydroxy-1,4-naphthoquinone analogues against food-borne bacteria. The antimicrobial activities of five fractions derived from the methanol extract of Lawsonia inermis leaves were evaluated against 7 food-borne bacteria. 2-Hydroxy-1,4-naphthoquinone was isolated by chromatographic analyses. 2-Hydroxy-1,4-naphthoquinone showed the strong activities against Bacillus cereus, Listeria monocytogenes, Salmonella enterica, Shigella sonnei, Staphylococcus epidermidis, and S. intermedius, but exerted no growth-inhibitory activities against S. typhimurium. The antimicrobial activities of the 2-hydroxy-1,4-naphthoquinone analogues were tested against 7 food-borne bacteria to establish structure-activity relationships. Hydroxyl (2-hydroxy-1,4-naphthoquinone and 5-hydroxy-1,4-naphthoquinone), methoxy (2-methoxy-1,4-naphthoquinone), and methyl (2-methyl-1,4-naphthoquinone, and 5-hydroxy-2-methyl-1,4-naphthoquinone) functional groups on the 1,4-naphthoquinone skeleton possessed potent activities, whereas bromo (2-bromo-1,4-naphthoquinone and 2,3-dibromo-1,4-naphthoquione) and chloro (2,3-dichloro-1,4-naphthoquinone) exhibited no activity against 7 food-borne bacteria. The L. inermis leaf extract and 2-hydroxy-1,4-naphthoquinone analogues should be useful as natural antimicrobial agents against food-borne bacteria. PMID:25829631

Yang, Ji-Yeon; Lee, Hoi-Seon

2015-04-01

113

On Distributed Key Distribution Centers and Unconditionally Secure Proactive Verifiable Secret Sharing Schemes Based on General Access Structure  

Microsoft Academic Search

A Key Distribution Center of a network is a server enabling private communications within groups of users. A Distributed Key Distri- bution Center is a set of servers that jointly realizes a Key Distribution Center. In this paper we build a robust Distributed Key Distribution Center Scheme secure against active and mobile adversary. We consider a general access structure for

Ventzislav Nikov; Svetla Nikova; Bart Preneel; Joos Vandewalle

2002-01-01

114

Structural and functional properties of heparin analogues obtained by chemical sulphation of Escherichia coli K5 capsular polysaccharide.  

PubMed Central

Capsular polysaccharide from Escherichia coli K5, with the basic structure (GlcA beta 1-4GlcNAc alpha 1-4)n, was chemically modified through N-deacetylation, N-sulphation and O-sulphation [Casu, Grazioli, Razi, Guerrini, Naggi, Torri, Oreste, Tursi, Zoppetti and Lindahl (1994) Carbohydr. Res. 263, 271-284]. Depending on the reaction conditions, the products showed different proportions of components with high affinity for antithrombin (AT). A high-affinity subfraction, M(r) approx. 36,000, was shown by near-UV CD, UV-absorption difference spectroscopy and fluorescence to cause conformational changes in the AT molecule very similar to those induced by high-affinity heparin. Fluorescence titrations demonstrated about two AT-binding sites per polysaccharide chain, each with a Kd of approx. 200 nM. The anti-(Factor Xa) activity was 170 units/mg, similar to that of the IIId international heparin standard and markedly higher than activities of previously described heparin analogues. Another preparation, M(r) approx. 13,000, of higher overall O-sulphate content, exhibited a single binding site per chain, with Kd approx. 1 microM, and an anti-(Factor Xa) activity of 70 units/mg. Compositional analysis of polysaccharide fractions revealed a correlation between the contents of -GlcA-GlcNSO3(3,6-di-OSO3)- disaccharide units and affinity for AT; the 3-O-sulphated GlcN unit has previously been identified as a marker component of the AT-binding pentasaccharide sequence in heparin. The abundance of the implicated disaccharide unit approximately equalled that of AT-binding sites in the 36,000-M(r) polysaccharide fraction, and approached one per high-affinity oligosaccharide (predominantly 10-12 monosaccharide units) isolated after partial depolymerization of AT-binding polysaccharide. These findings suggest that the modified bacterial polysaccharide interacts with AT and promotes its anticoagulant action in a manner similar to that of heparin. PMID:7626010

Razi, N; Feyzi, E; Björk, I; Naggi, A; Casu, B; Lindahl, U

1995-01-01

115

Lactam-stabilized helical analogues of the analgesic ?-conotoxin KIIIA  

PubMed Central

?-Conotoxin KIIIA (?-KIIIA) blocks mammalian voltage-gated sodium channels (VGSCs) and is a potent analgesic following systemic administration in mice. Previous structure-activity studies of ?-KIIIA identified a helical pharmacophore for VGSC blockade. This suggested a route for designing truncated analogues of ?-KIIIA by incorporating the key residues into an ?-helical scaffold. As (i, i+4) lactam bridges constitute a proven approach for stabilizing ?-helices, we designed and synthesized six truncated analogues of ?-KIIIA containing single lactam bridges at various locations. The helicity of these lactam analogues was analysed by NMR spectroscopy, and their activities were tested against mammalian VGSC subtypes NaV1.1 through 1.7. Two of the analogues, Ac-cyclo9/13[Asp9,Lys13]KIIIA7–14 and Ac-cyclo9/13[Lys9,Asp13]KIIIA7–14, displayed µM activity against VGSC subtypes NaV1.2 and NaV1.6; importantly, the subtype selectivity profile for these peptides matched that of ?-KIIIA. Our study highlights structure-activity relationships within these helical mimetics and provides a basis for the design of additional truncated peptides as potential analgesics. PMID:21962108

Khoo, Keith K.; Wilson, Michael J.; Smith, Brian J.; Zhang, Min-Min; Gulyas, Joszef; Yoshikami, Doju; Rivier, Jean E.; Bulaj, Grzegorz; Norton, Raymond S.

2011-01-01

116

OptZyme: Computational Enzyme Redesign Using Transition State Analogues  

PubMed Central

OptZyme is a new computational procedure for designing improved enzymatic activity (i.e., kcat or kcat/KM) with a novel substrate. The key concept is to use transition state analogue compounds, which are known for many reactions, as proxies for the typically unknown transition state structures. Mutations that minimize the interaction energy of the enzyme with its transition state analogue, rather than with its substrate, are identified that lower the transition state formation energy barrier. Using Escherichia coli ?-glucuronidase as a benchmark system, we confirm that KM correlates (R2?=?0.960) with the computed interaction energy between the enzyme and the para-nitrophenyl- ?, D-glucuronide substrate, kcat/KM correlates (R2?=?0.864) with the interaction energy of the transition state analogue, 1,5-glucarolactone, and kcat correlates (R2?=?0.854) with a weighted combination of interaction energies with the substrate and transition state analogue. OptZyme is subsequently used to identify mutants with improved KM, kcat, and kcat/KM for a new substrate, para-nitrophenyl- ?, D-galactoside. Differences between the three libraries reveal structural differences that underpin improving KM, kcat, or kcat/KM. Mutants predicted to enhance the activity for para-nitrophenyl- ?, D-galactoside directly or indirectly create hydrogen bonds with the altered sugar ring conformation or its substituents, namely H162S, L361G, W549R, and N550S. PMID:24116038

Grisewood, Matthew J.; Gifford, Nathanael P.; Pantazes, Robert J.; Li, Ye; Cirino, Patrick C.; Janik, Michael J.; Maranas, Costas D.

2013-01-01

117

Identification of a Key Structural Element for Protein Folding Within ?-Hairpin Turns  

Microsoft Academic Search

Specific residues in a polypeptide may be key contributors to the stability and foldability of the unique native structure. Identification and prediction of such residues is, therefore, an important area of investigation in solving the protein folding problem. Atypical main-chain conformations can help identify strains within a folded protein, and by inference, positions where unique amino acids may have a

Jaewon Kim; Stephen R. Brych; Jihun Lee; Timothy M. Logan; Michael Blaber

2003-01-01

118

Enhancing the functional annotation of PDB structures in PDBsum using key figures extracted from the literature  

Microsoft Academic Search

Motivation: The Protein Data Bank (PDB) contains over 43 800 experimentally determined 3D models of macromolecular structures and their complexes. Each 3D model reveals something interesting and important about the given molecule's function and biological significance. Usually the best source of this information is the original article describing it, and it is often possible to discern the key aspects of

Roman A. Laskowski

2007-01-01

119

Glutamate provides a key structural contact between reticulon-4 (Nogo-66) and phosphocholine  

E-print Network

Glutamate provides a key structural contact between reticulon-4 (Nogo-66) and phosphocholine Ali form 9 May 2014 Accepted 16 May 2014 Available online 24 May 2014 Keywords: Reticulon Nogo-66 Membrane inhibitor (Nogo). This protein contains a span of 66 amino acids (Nogo-66) flanked by two membrane helices

Weiss, Gregory A.

120

Structural Insights into the Inhibition of Cytosolic 5?Nucleotidase II (cN-II) by Ribonucleoside 5?Monophosphate Analogues  

Microsoft Academic Search

Cytosolic 5?-nucleotidase II (cN-II) regulates the intracellular nucleotide pools within the cell by catalyzing the dephosphorylation of 6-hydroxypurine nucleoside 5?-monophosphates. Beside this physiological function, high level of cN-II expression is correlated with abnormal patient outcome when treated with cytotoxic nucleoside analogues. To identify its specific role in the resistance phenomenon observed during cancer therapy, we screened a particular class of

Franck Gallier; Perrine Lallemand; Maïa Meurillon; Lars P. Jordheim; Charles Dumontet; Christian Périgaud; Corinne Lionne; Suzanne Peyrottes; Laurent Chaloin

2011-01-01

121

Preliminary results of a multi-scale structural analisys in an analogue carbonate reservoir (Hyblean Plateau, Sicily, Italy)  

NASA Astrophysics Data System (ADS)

With the aim of studying the multi-scale fault architecture and permeability in hydrocarbon-rich porous carbonate rocks, we are currently involved in a project focused on the structural analysis of fractured and faulted platform-to-ramp carbonates cropping out in the Hyblean Plateau (Sicily, Italy). The Hyblean Plateau is part of the Maghrebian foreland and forms the northern portion of the African plate. The plateau is a NE-oriented structural high crosscut by a large-scale N10°-20°E oriented strike-slip fault system, named Scicli-Ragusa, which was affected by right-lateral kinematics during the Upper Miocene-Lower Pliocene. Some authors documented a recent activity of the Scicli-Ragusa fault system, during the Quaternary, characterized by left-lateral kinematics. The portion of the Hyblean Plateau crosscut by this fault system represents an excellent example of an outcropping analogue of a fractured carbonate reservoir. By taking advantage of the several oil shows located along the Scicli-Ragusa fault system, we combine stratigraphic-structural analyses, both at outcrop and microscopic scales, to assess the structural control exerted by faults and fractures on hydrocarbon migration and storage. The field work focused on the geological mapping, at 1:10.000 scale, on detailed stratigraphic characterization of the outcropping layered carbonates (Ragusa Fm.) and on traditional faults and fractures analysis. Sample collection was also performed in order to conduct, in the laboratory, optical microscope and image analyses. The Oligo-Miocenic Ragusa Fm. is comprised of two main members: i) the lower Leonardo Member, which is characterised by well-cemented carbonate packstones intercalated with marl-rich levels; ii) the upper Irminio Member, characterised by an alternation of well-cemented and poorly-cemented grainstones/packstones. According to both orientations and kinematics, we grouped the fault segments of the Scicli-Ragusa fault system into three major sets: (i) NNE-striking faults with predominant right-lateral kinematics, (ii) ENE-striking faults with left-lateral kinematics, and (iii) NE-striking faults characterized by normal slip. Conversely, based on the fault attributes we subdivided the outcropping faults into four main categories: (i) Major faults, comprised of well-developed fault cores (made up of cataclastic rocks and main slip surfaces) flanked by thicker fault damage zones, which are up to 18 km-long and have throws in the order of 100's of meters. (ii) Medium faults containing thin and discontinuous fault cores of brecciated and cataclastic fault rocks and through-going slip surfaces encompassed within the fault damage zones, which are long up to several 100's of meters and have throws up to 10's of meters. (iii) Small faults made up of isolated and discontinuous fault cores of faults breccias and through-going slip surfaces, which are up to a few m-long and have throws in order of several 10's of cm and a few meters. (iv) Incipient faults consist, predominantly, of sheared pre-existing fractures confined within the individual carbonate beds; the maximum throw < 10 cm. The meso-structural analysis performed to define the background deformation allowed us to identify mainly three different typology of structures: i) joints, ii) stylolites, and iii) shear bands. On the basis of their abutting relationships first originated bed-parallel stylolites and then two coeval sets of bed perpendicular joints. Shear bands nucleated by shearing of previously formed bed-parallel and bed-perpendicular structures. Another important data came out from preliminary microscope analysis carried out within mines of tar rich carbonates. Here, shear bands within porous layers behaved as a seal for oil migration whereas joints, localized in well cemented layers, acted as conduct for hydrocarbons. Finally, as planned work, we are going to combine fault architecture data with petrophysical analyses conducted on samples belonging to different structural domains in order to define hydraulic behaviours of the studied faults.

Cilona, Antonino; Agosta, Fabrizio; Criscenti, Alessandro; Dipasquale, Mario; Giunta, Giuseppe; Napoli, Giuseppe; Occhipinti, Rosario; Renda, Pietro; Tondi, Emanuele

2010-05-01

122

Structure-activity relationship studies of 4-[2-(diphenylmethoxy)ethyl]-1-benzylpiperidine derivatives and their N-analogues: evaluation of O-and N-analogues and their binding to monoamine transporters.  

PubMed

In our effort to develop a pharmacotherapy for the treatment of cocaine addiction, we embarked on synthesizing novel molecules targeting the dopamine transporter (DAT) molecule in the brain as DAT has been implicated strongly in the reinforcing effect of cocaine. Our previously developed DAT-selective piperidine analogue, 4-[2-(diphenylmethoxy)ethyl]-1-benzylpiperidine, was the basis for our current structure-activity relationship (SAR) studies exploring the significance of the contribution of the benzhydryl O- and N-atoms in these molecules in interacting with the DAT. Thus, we replaced the benzhydryl O-atom with an N-atom, altered the location of the benzhydryl N-atom to an adjacent position, and in one other occasion converted the benzhydryl O-ether linkage into an oxime-type derivative. Furthermore, we also evaluated the important contribution of the piperidine N-atom to binding by altering its pK(a) value chemically. Novel analogues were tested for potency in inhibiting [3H]WIN 35,428, [3H]citalopram, and [3H]nisoxetine binding at the DAT, serotonin transporter (SERT), and norepinepherine transporter (NET). [3H]DA was used to measure DA reuptake inhibition. The results indicated that the benzhydryl O- and N-atoms are exchangeable for the most part. On the other hand, an enhanced interaction with the SERT was observed when the benzhydryl N-atom moved to an adjacent position (21a; DAT (IC(50)) = 19.7, SERT (IC(50)) = 137 nM, NET (IC(50)) = 1111 nM). In either cases, further alkylation of the N-atom reduced the activity for the transporter. The presence of a powerful electron-withdrawing cyano group in compound 5d expectedly produced the most potent and selective ligand for the DAT (DAT (IC(50)) = 3.7 nM, DAT/SERT = 615). Selected compounds were further analyzed in the dopamine reuptake inhibition assay. Preliminary behavioral assessment of some of the selected compounds in mice indicated that these compounds are much less stimulating when compared with cocaine at comparable doses. In drug-discrimination studies these selected compounds incompletely generalized from the cocaine stimulus in mice trained to discriminate 10 mg/kg cocaine from vehicle. PMID:11300876

Dutta, A K; Fei, X S; Beardsley, P M; Newman, J L; Reith, M E

2001-03-15

123

Key factors for successful generation of protein-fragment structures requirement on protein, crystals, and technology.  

PubMed

In the past two decades, fragment-based approaches have evolved as a predominant strategy in lead discovery. The availability of structural information on the interaction geometries of binding fragments is key to successful structure-guided fragment-to-lead evolution. In this chapter, we illustrate methodological advances for protein-fragment crystal structure generation in order to offer general lessons on the importance of fragment properties and the most appropriate crystallographic setup to evaluate them. We analyze elaborate protocols, methods, and clues applied to challenging complex formation projects. The results should assist medicinal chemists to select the most promising targets and strategies for fragment-based crystallography as well as provide a tutorial to structural biologists who attempt to determine protein-fragment structures. PMID:21371587

Böttcher, Jark; Jestel, Anja; Kiefersauer, Reiner; Krapp, Stephan; Nagel, Susanna; Steinbacher, Stefan; Steuber, Holger

2011-01-01

124

Structural insights into the inhibition of cytosolic 5'-nucleotidase II (cN-II) by ribonucleoside 5'-monophosphate analogues.  

PubMed

Cytosolic 5'-nucleotidase II (cN-II) regulates the intracellular nucleotide pools within the cell by catalyzing the dephosphorylation of 6-hydroxypurine nucleoside 5'-monophosphates. Beside this physiological function, high level of cN-II expression is correlated with abnormal patient outcome when treated with cytotoxic nucleoside analogues. To identify its specific role in the resistance phenomenon observed during cancer therapy, we screened a particular class of chemical compounds, namely ribonucleoside phosphonates to predict them as potential cN-II inhibitors. These compounds incorporate a chemically and enzymatically stable phosphorus-carbon linkage instead of a regular phosphoester bond. Amongst them, six compounds were predicted as better ligands than the natural substrate of cN-II, inosine 5'-monophosphate (IMP). The study of purine and pyrimidine containing analogues and the introduction of chemical modifications within the phosphonate chain has allowed us to define general rules governing the theoretical affinity of such ligands. The binding strength of these compounds was scrutinized in silico and explained by an impressive number of van der Waals contacts, highlighting the decisive role of three cN-II residues that are Phe 157, His 209 and Tyr 210. Docking predictions were confirmed by experimental measurements of the nucleotidase activity in the presence of the three best available phosphonate analogues. These compounds were shown to induce a total inhibition of the cN-II activity at 2 mM. Altogether, this study emphasizes the importance of the non-hydrolysable phosphonate bond in the design of new competitive cN-II inhibitors and the crucial hydrophobic stacking promoted by three protein residues. PMID:22174667

Gallier, Franck; Lallemand, Perrine; Meurillon, Maïa; Jordheim, Lars P; Dumontet, Charles; Périgaud, Christian; Lionne, Corinne; Peyrottes, Suzanne; Chaloin, Laurent

2011-12-01

125

Structural Insights into the Inhibition of Cytosolic 5?-Nucleotidase II (cN-II) by Ribonucleoside 5?-Monophosphate Analogues  

PubMed Central

Cytosolic 5?-nucleotidase II (cN-II) regulates the intracellular nucleotide pools within the cell by catalyzing the dephosphorylation of 6-hydroxypurine nucleoside 5?-monophosphates. Beside this physiological function, high level of cN-II expression is correlated with abnormal patient outcome when treated with cytotoxic nucleoside analogues. To identify its specific role in the resistance phenomenon observed during cancer therapy, we screened a particular class of chemical compounds, namely ribonucleoside phosphonates to predict them as potential cN-II inhibitors. These compounds incorporate a chemically and enzymatically stable phosphorus-carbon linkage instead of a regular phosphoester bond. Amongst them, six compounds were predicted as better ligands than the natural substrate of cN-II, inosine 5?-monophosphate (IMP). The study of purine and pyrimidine containing analogues and the introduction of chemical modifications within the phosphonate chain has allowed us to define general rules governing the theoretical affinity of such ligands. The binding strength of these compounds was scrutinized in silico and explained by an impressive number of van der Waals contacts, highlighting the decisive role of three cN-II residues that are Phe 157, His 209 and Tyr 210. Docking predictions were confirmed by experimental measurements of the nucleotidase activity in the presence of the three best available phosphonate analogues. These compounds were shown to induce a total inhibition of the cN-II activity at 2 mM. Altogether, this study emphasizes the importance of the non-hydrolysable phosphonate bond in the design of new competitive cN-II inhibitors and the crucial hydrophobic stacking promoted by three protein residues. PMID:22174667

Meurillon, Maïa; Jordheim, Lars P.; Dumontet, Charles; Périgaud, Christian; Lionne, Corinne; Peyrottes, Suzanne; Chaloin, Laurent

2011-01-01

126

Synthesis and SAR of vinca alkaloid analogues  

Microsoft Academic Search

Versatile intermediates 12?-iodovinblastine, 12?-iodovincristine and 11?-iodovinorelbine were utilized as substrates for transition metal based chemistry which led to the preparation of novel analogues of the vinca alkaloids. The synthesis of key iodo intermediates, their transformation into final products, and the SAR based upon HeLa and MCF-7 cell toxicity assays is presented. Selected analogues 27 and 36 show promising anticancer activity

Matthew E. Voss; Jeffery M. Ralph; Dejian Xie; David D. Manning; Xinchao Chen; Anthony J. Frank; Andrew J. Leyhane; Lei Liu; Jason M. Stevens; Cheryl Budde; Matthew D. Surman; Thomas Friedrich; Denise Peace; Ian L. Scott; Mark Wolf; Randall Johnson

2009-01-01

127

The crystal structure of myelin oligodendrocyte glycoprotein, a key autoantigen in multiple sclerosis  

Microsoft Academic Search

Myelin oligodendrocyte glycoprotein (MOG) is a key CNS-specific autoantigen for primary demyelination in multiple sclerosis. Although the disease-inducing role of MOG has been established, its precise function in the CNS remains obscure. To gain new insights into the physiological and immunopathological role of MOG, we determined the 1.8-Å crystal structure of the MOG extracellular domain (MOGED). MOGED adopts a classical

Craig S. Clements; Hugh H. Reid; Travis Beddoe; Fleur E. Tynan; Matthew A. Perugini; Terrance G. Johns; Claude C. A. Bernard; Jamie Rossjohn

2003-01-01

128

Effects of Vegetation Structure and Elevation on Lower Keys Marsh Rabbit Density  

E-print Network

for the degree of MASTER OF SCIENCE Approved by: Co-Chairs of Committee, Nova J. Silvy Roel R. Lopez Committee Member, Donald S. Davis Interim Head of Department, John B. Carey December 2011 Major Subject: Wildlife and Fisheries Sciences iii... ABSTRACT Effects of Vegetation Structure and Elevation on Lower Keys Marsh Rabbit Density. (December 2011) Angela Jane Dedrickson, B.S., Texas A&M University Co-Chairs of Advisory Committee: Dr. Nova J. Silvy...

Dedrickson, Angela

2012-02-14

129

One pot synthesis, structural and spectral analysis of some symmetrical curcumin analogues catalyzed by calcium oxide under microwave irradiation  

NASA Astrophysics Data System (ADS)

A series of sixteen number of curcumin analogues have been synthesized under microwave irradiation using calcium oxide as a catalyst. The synthesized compounds have been characterized using FT-IR, MS, elemental analysis, 1H and 13C NMR spectroscopic techniques. The UV-Vis absorption studies for these compounds have been studied in order to provide the electronic transitions taking place in the molecule. When compared to the curcumin ((1E,4Z,6E)-5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,4,6-trien-3-one), the absorption maxima, ?max for all the synthesized curcumin analogues with a variety of substituents gets blue shifted i.e., hypsochromic shift was observed. This shift may be assigned to the change of dipole moment within the solvated molecule. Theoretical calculations regarding the optimization of the synthesized molecules, electronic properties like highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) and mapped electron density surface diagrams were done. The geometrical energy, dipole moments and heat of formation values have also been calculated using the ArgusLab package by AM1 semi-empirical method.

Elavarasan, S.; Bhakiaraj, D.; Chellakili, B.; Elavarasan, T.; Gopalakrishnan, M.

2012-11-01

130

Issues of geologically-focused situational awareness in robotic planetary missions: Lessons from an analogue mission at Mistastin Lake impact structure, Labrador, Canada  

NASA Astrophysics Data System (ADS)

Remote robotic data provides different information than that obtained from immersion in the field. This significantly affects the geological situational awareness experienced by members of a mission control science team. In order to optimize science return from planetary robotic missions, these limitations must be understood and their effects mitigated to fully leverage the field experience of scientists at mission control.Results from a 13-day analogue deployment at the Mistastin Lake impact structure in Labrador, Canada suggest that scale, relief, geological detail, and time are intertwined issues that impact the mission control science team's effectiveness in interpreting the geology of an area. These issues are evaluated and several mitigation options are suggested. Scale was found to be difficult to interpret without the reference of known objects, even when numerical scale data were available. For this reason, embedding intuitive scale-indicating features into image data is recommended. Since relief is not conveyed in 2D images, both 3D data and observations from multiple angles are required. Furthermore, the 3D data must be observed in animation or as anaglyphs, since without such assistance much of the relief information in 3D data is not communicated. Geological detail may also be missed due to the time required to collect, analyze, and request data.We also suggest that these issues can be addressed, in part, by an improved understanding of the operational time costs and benefits of scientific data collection. Robotic activities operate on inherently slow time-scales. This fact needs to be embraced and accommodated. Instead of focusing too quickly on the details of a target of interest, thereby potentially minimizing science return, time should be allocated at first to more broad data collection at that target, including preliminary surveys, multiple observations from various vantage points, and progressively smaller scale of focus. This operational model more closely follows techniques employed by field geologists and is fundamental to the geologic interpretation of an area. Even so, an operational time cost/benefit analyses should be carefully considered in each situation, to determine when such comprehensive data collection would maximize the science return.Finally, it should be recognized that analogue deployments cannot faithfully model the time scales of robotic planetary missions. Analogue missions are limited by the difficulty and expense of fieldwork. Thus, analogue deployments should focus on smaller aspects of robotic missions and test components in a modular way (e.g., dropping communications constraints, limiting mission scope, focusing on a specific problem, spreading the mission over several field seasons, etc.).

Antonenko, I.; Osinski, G. R.; Battler, M.; Beauchamp, M.; Cupelli, L.; Chanou, A.; Francis, R.; Mader, M. M.; Marion, C.; McCullough, E.; Pickersgill, A. E.; Preston, L. J.; Shankar, B.; Unrau, T.; Veillette, D.

2013-07-01

131

Synthesis and Evaluation of ?-Thymidine Analogues as Novel Antimalarials  

PubMed Central

Plasmodium falciparum thymidylate kinase (PfTMPK) is a key enzyme in pyrimidine nucleotide biosynthesis. 3-Trifluoromethyl-4-chloro-phenyl-urea-?-thymidine has been reported as an inhibitor of Mycobacterium tuberculosis TMPK (MtTMPK). Starting from this point, we designed, synthesized and evaluated a number of thymidine analogues as antimalarials. Both 5?-urea-?- and ?-thymidine derivatives were moderate inhibitors of PfTMPK and furthermore showed moderate inhibition of parasite growth. The structure of several enzyme–inhibitor complexes provides a basis for improved inhibitor design. However, we found that certain 5?-urea-?-thymidine analogues had antimalarial activity where inhibition of PfTMPK is not the major mode of action. Optimization of this series resulted in a compound with potent antimalarial activity (EC50 = 28 nM; CC50 = 29 ?M). PMID:23240776

2012-01-01

132

New Insights into the Design of Inhibitors of Human S-Adenosylmethionine Decarboxylase: Studies of Adenine C8 Substitution in Structural Analogues of S-Adenosylmethionine†  

PubMed Central

S-Adenosylmethionine decarboxylase (AdoMetDC) is a critical enzyme in the polyamine biosynthetic pathway and depends on a pyruvoyl group for the decarboxylation process. The crystal structures of the enzyme with various inhibitors at the active site have shown that the adenine base of the ligands adopts an unusual syn conformation when bound to the enzyme. To determine whether compounds that favor the syn conformation in solution would be more potent AdoMetDC inhibitors, several series of AdoMet substrate analogues with a variety of substituents at the 8-position of adenine were synthesized and analyzed for their ability to inhibit hAdoMetDC. The biochemical analysis indicated that an 8-methyl substituent resulted in more potent inhibitors, yet most other 8-substitutions provided no benefit over the parent compound. To understand these results, we used computational modeling and X-ray crystallography to study C8-substituted adenine analogues bound in the active site. PMID:19209891

2009-01-01

133

Convergent chemoenzymatic synthesis of a library of glycosylated analogues of pramlintide: structure-activity relationships for amylin receptor agonism.  

PubMed

Pramlintide (Symlin®), a synthetic analogue of the naturally occurring pancreatic hormone amylin, is currently used with insulin in adjunctive therapy for type 1 and type 2 diabetes mellitus. Herein we report a systematic study into the effect that N-glycosylation of pramlintide has on activation of amylin receptors. A highly efficient convergent synthetic route, involving a combination of solid phase peptide synthesis and enzymatic glycosylation, delivered a library of N-glycosylated variants of pramlintide bearing either GlcNAc, the core N-glycan pentasaccharide [Man3(GlcNAc)2] or a complex biantennary glycan [(NeuAcGalGlcNAcMan)2Man(GlcNAc)2] at each of its six asparagine residues. The majority of glycosylated versions of pramlintide were potent receptor agonists, suggesting that N-glycosylation may be used as a tool to optimise the pharmacokinetic properties of pramlintide and so deliver improved therapeutic agents for the treatment of diabetes and obesity. PMID:25030939

Kowalczyk, Renata; Brimble, Margaret A; Tomabechi, Yusuke; Fairbanks, Antony J; Fletcher, Madeleine; Hay, Debbie L

2014-11-01

134

G-Reflectors: Analogues of Householder Transformations in Scalar Product Spaces  

E-print Network

G-Reflectors: Analogues of Householder Transformations in Scalar Product Spaces D. Steven Mackey. Key words. scalar product, bilinear, sesquilinear, orthosymmetric, isotropic, Householder Niloufer Mackey Fran¸coise Tisseur Abstract We characterize the analogues of Householder transformations

Tisseur, Francoise

135

Strong Nonadditivity as a Key Structure–Activity Relationship Feature: Distinguishing Structural Changes from Assay Artifacts  

PubMed Central

Nonadditivity in protein–ligand affinity data represents highly instructive structure–activity relationship (SAR) features that indicate structural changes and have the potential to guide rational drug design. At the same time, nonadditivity is a challenge for both basic SAR analysis as well as many ligand-based data analysis techniques such as Free-Wilson Analysis and Matched Molecular Pair analysis, since linear substituent contribution models inherently assume additivity and thus do not work in such cases. While structural causes for nonadditivity have been analyzed anecdotally, no systematic approaches to interpret and use nonadditivity prospectively have been developed yet. In this contribution, we lay the statistical framework for systematic analysis of nonadditivity in a SAR series. First, we develop a general metric to quantify nonadditivity. Then, we demonstrate the non-negligible impact of experimental uncertainty that creates apparent nonadditivity, and we introduce techniques to handle experimental uncertainty. Finally, we analyze public SAR data sets for strong nonadditivity and use recourse to the original publications and available X-ray structures to find structural explanations for the nonadditivity observed. We find that all cases of strong nonadditivity (??pKi and ??pIC50 > 2.0 log units) with sufficient structural information to generate reasonable hypothesis involve changes in binding mode. With the appropriate statistical basis, nonadditivity analysis offers a variety of new attempts for various areas in computer-aided drug design, including the validation of scoring functions and free energy perturbation approaches, binding pocket classification, and novel features in SAR analysis tools. PMID:25760829

2015-01-01

136

Strong nonadditivity as a key structure-activity relationship feature: distinguishing structural changes from assay artifacts.  

PubMed

Nonadditivity in protein-ligand affinity data represents highly instructive structure-activity relationship (SAR) features that indicate structural changes and have the potential to guide rational drug design. At the same time, nonadditivity is a challenge for both basic SAR analysis as well as many ligand-based data analysis techniques such as Free-Wilson Analysis and Matched Molecular Pair analysis, since linear substituent contribution models inherently assume additivity and thus do not work in such cases. While structural causes for nonadditivity have been analyzed anecdotally, no systematic approaches to interpret and use nonadditivity prospectively have been developed yet. In this contribution, we lay the statistical framework for systematic analysis of nonadditivity in a SAR series. First, we develop a general metric to quantify nonadditivity. Then, we demonstrate the non-negligible impact of experimental uncertainty that creates apparent nonadditivity, and we introduce techniques to handle experimental uncertainty. Finally, we analyze public SAR data sets for strong nonadditivity and use recourse to the original publications and available X-ray structures to find structural explanations for the nonadditivity observed. We find that all cases of strong nonadditivity (??pKi and ??pIC50 > 2.0 log units) with sufficient structural information to generate reasonable hypothesis involve changes in binding mode. With the appropriate statistical basis, nonadditivity analysis offers a variety of new attempts for various areas in computer-aided drug design, including the validation of scoring functions and free energy perturbation approaches, binding pocket classification, and novel features in SAR analysis tools. PMID:25760829

Kramer, Christian; Fuchs, Julian E; Liedl, Klaus R

2015-03-23

137

Comprehensive analysis of three-dimensional activity cliffs formed by kinase inhibitors with different binding modes and cliff mapping of structural analogues.  

PubMed

Kinases are among the structurally most extensively characterized therapeutic targets. For many kinases, X-ray structures of inhibitor complexes are publicly available. We have identified all three-dimensional activity cliffs (3D-cliffs) formed by kinase inhibitors. More than 1300 X-ray structures of unique kinase-inhibitor complexes and associated activity data were analyzed. On the basis of binding mode comparison and 3D similarity calculations, 105 3D-cliffs were detected for type I, type II, or type III inhibitors of 13 different kinases. Many of these activity cliffs revealed clear interaction differences between highly and weakly potent inhibitors. More than 200 structural analogues of 3D-cliff compounds were identified whose structure-activity relationships (SARs) can be further explored in three dimensions on the basis of the corresponding 3D-cliffs. In addition to SAR exploration, 3D-cliffs provide useful interaction hypotheses for structure-based design. The kinase inhibitor and activity cliff information is made freely available as a part of our study. PMID:25054653

Furtmann, Norbert; Hu, Ye; Bajorath, Jürgen

2015-01-01

138

Pseudocyanides of sanguinarine and chelerythrine and their series of structurally simple analogues as new anticancer lead compounds: Cytotoxic activity, structure-activity relationship and apoptosis induction.  

PubMed

6-Cyano dihydrosanguinarine (CNS) and 6-cyano dihydrochelerythrine (CNC) are respectively artificial derivatives of sanguinarine and chelerythrine, two anticancer quaternary benzo[c]phenanthridine alkaloids (QBAs) while 1-cyano-2-aryl-1,2,3,4-tetrahydroisoquinolines (CATHIQs) are a class of structurally simple analogues of CNS or CNC. This study investigated the inhibition activity of CNS, CNC and CATHIQs on cancer cells, apoptosis induction as well as their preliminary SAR. The results showed that CNS and 18 out of CATHIQs showed IC50 values of 0.53 and 0.62-2.24?M against NB4 and 1.53 and 2.99-11.17?M against MKN-45 cells, respectively, superior to a standard anticancer drug cis-platinum with IC50 of 2.39 and 11.36?M. CNC showed a higher activity against NB4 cells (IC50=1.85?M) and a moderate activity against MKN-45 cells (IC50=12.72?M). Among all CATHIQs, 2 and 17 gave the highest activity against NB4 cells and MKN-45 cells (IC50=0.62 and 2.99?M), respectively. DAPI staining, AO/EB staining and ultrastructure analysis of cells demonstrated that CATHIQs were able to induce apoptosis of the cells in a concentration-dependent manner. SAR showed that substitution patterns on the N-aromatic ring significantly influenced the activity of CATHIQs. The general trend was that the introduction of electron-withdrawing substituents like halogen atom, nitro, trifluoromethyl led to a significant improvement of the activity, while the presence of electron-donating groups like methyl, methoxyl caused a reduction of the activity. In most cases, the 2' site was the most favorable substitution position for the improvement of the activity. Thus, the present results strongly suggested that QBA-type pseudocyanides may serve as potential alternatives of anticancer QBAs while CATHIQs should be a class of promising lead compounds for the development of new QBA-like-type anticancer drugs. CNS exhibited the highest cytotoxicities with IC50 values of 0.53?M on NB4 cells and 1.53?M on MKN-45 cells. PMID:25444843

Cao, Fang-Jun; Yang, Rui; Lv, Chao; Ma, Qun; Lei, Ming; Geng, Hui-Ling; Zhou, Le

2015-01-25

139

Structural requisites of 2-(p-chlorophenoxy)propionic acid analogues for activity on native rat skeletal muscle chloride conductance and on heterologously expressed CLC-1.  

PubMed

(1) The 2-(p-chlorophenoxy)propionic acid (CPP) modulates in a stereoselective manner the macroscopic chloride conductance (gCl), the electrical parameter sustained by the CLC-1 channel, of skeletal muscle. In order to determine the structural requirements for modulating native gCl and to identify high-affinity ligands, the effects of newly synthesised CPP analogues have been evaluated on gCl of rat EDL muscle fibres by means of the two-microelectrode current-clamp technique. (2) Each type of the following independent modification of CPP structure led to a three- to 10-fold decrease or to a complete lack of gCl-blocking activity: replacement of the electron-attractive chlorine atom of the aromatic ring, substitution of the oxygen atom of the phenoxy group, modification at the chiral centre and substitution of the carboxylic function with a phosphonate one. (3) The analogues bearing a second chlorophenoxy group on the asymmetric carbon atom showed a significant gCl-blocking activity. Similar to racemate CPP, the analogue with this group, spaced by an alkyl chain formed by three methylenic groups, blocked gCl by 45% at 100 micro M. (4) These latter derivatives were tested on heterelogously expressed CLC-1 performing inside-out patch-clamp recordings to further define how interaction between drug and channel protein could take place. Depending on the exact chemical nature of modification, these derivatives strongly blocked CLC-1 with K(D) values at -140 mV ranging from about 4 to 180 micro M. (5) In conclusion, we identified four molecular determinants pivotal for the interaction with the binding site on muscle CLC-1 channels: (a) the carboxylic group that confers the optimal acidity and the negative charge; (b) the chlorophenoxy moiety that might interact with a hydrophobic pocket; (c) the chiral centre that allows the proper spatial disposition of the molecule; (d) an additional phenoxy group that remarkably stabilises the binding by interacting with a second hydrophobic pocket. PMID:12890704

Liantonio, Antonella; De Luca, Annamaria; Pierno, Sabata; Didonna, Maria Paola; Loiodice, Fulvio; Fracchiolla, Giuseppe; Tortorella, Paolo; Antonio, Laghezza; Bonerba, Elisabetta; Traverso, Sonia; Elia, Laura; Picollo, Alessandra; Pusch, Michael; Camerino, Diana Conte

2003-08-01

140

1.45 A resolution crystal structure of recombinant PNP in complex with a pM multisubstrate analogue inhibitor bearing one feature of the postulated transition state  

SciTech Connect

Low molecular mass purine nucleoside phosphorylases (PNPs, E.C. 2.4.2.1) are homotrimeric enzymes that are tightly inhibited by immucillins. Due to the positive charge on the ribose like part (iminoribitol moiety) and protonation of the N7 atom of the purine ring, immucillins are believed to act as transition state analogues. Over a wide range of concentrations, immucillins bind with strong negative cooperativity to PNPs, so that only every third binding site of the enzyme is occupied (third-of-the-sites binding). 9-(5',5'-difluoro-5'-phosphonopentyl)-9-deazaguanine (DFPP-DG) shares with immucillins the protonation of the N7, but not the positive charge on the ribose like part of the molecule. We have previously shown that DFPP-DG interacts with PNPs with subnanomolar inhibition constant. Here, we report additional biochemical experiments to demonstrate that the inhibitor can be bound with the same K{sub d} ({approx}190 pM) to all three substrate binding sites of the trimeric PNP, and a crystal structure of PNP in complex with DFPP-DG at 1.45 A resolution, the highest resolution published for PNPs so far. The crystals contain the full PNP homotrimer in the asymmetric unit. DFPP-DG molecules are bound in superimposable manner and with full occupancies to all three PNP subunits. Thus the postulated third-of-the-sites binding of immucillins should be rather attribute to the second feature of the transition state, ribooxocarbenium ion character of the ligand or to the coexistence of both features characteristic for the transition state. The DFPP-DG/PNP complex structure confirms the earlier observations, that the loop from Pro57 to Gly66 covering the phosphate-binding site cannot be stabilized by phosphonate analogues. The loop from Glu250 to Gln266 covering the base-binding site is organized by the interactions of Asn243 with the Hoogsteen edge of the purine base of analogues bearing one feature of the postulated transition state (protonated N7 position).

Chojnowski, Grzegorz [Department of Biophysics, Institute of Experimental Physics, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw (Poland) [Department of Biophysics, Institute of Experimental Physics, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw (Poland); International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw (Poland); Breer, Katarzyna; Narczyk, Marta; Wielgus-Kutrowska, Beata [Department of Biophysics, Institute of Experimental Physics, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw (Poland)] [Department of Biophysics, Institute of Experimental Physics, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw (Poland); Czapinska, Honorata [International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw (Poland)] [International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw (Poland); Hashimoto, Mariko; Hikishima, Sadao; Yokomatsu, Tsutomu [School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392 (Japan)] [School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392 (Japan); Bochtler, Matthias [International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw (Poland) [International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw (Poland); Schools of Chemistry and Biosciences, Park Place, CF10 3AT Cardiff (United Kingdom); Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstr. 108, 01309 Dresden (Germany); Girstun, Agnieszka; Staron, Krzysztof [Department of Molecular Biology, Institute of Biochemistry, University of Warsaw, Miecznikowa 1, 02-096 Warsaw (Poland)] [Department of Molecular Biology, Institute of Biochemistry, University of Warsaw, Miecznikowa 1, 02-096 Warsaw (Poland); Bzowska, Agnieszka, E-mail: abzowska@biogeo.uw.edu.pl [Department of Biophysics, Institute of Experimental Physics, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw (Poland)] [Department of Biophysics, Institute of Experimental Physics, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw (Poland)

2010-01-01

141

Low-Melting Imidazolium-Based Salts with the Paramagnetic Reineckate-Analogue Anion [Cr(NCS)4(bipy)](-) (bipy = 2,2'-Bipyridine): Syntheses, Properties, and Structures.  

PubMed

In order to investigate the potential ionic liquid properties of Reineckate-analogue materials, four new salts, consisting of the heteroleptic [Cr(NCS)4(bipy)](-) complex anion and imidazolium-based cations A(+) = 1-ethyl-3-methylimidazolium, 1-n-butyl-3-methylimidazolium, pentamethylimidazolium, and 1,3-dimethyl-2,4,5-triphenylimidazolium, were investigated. Their structures were established by single-crystal X-ray diffraction. The compounds are paramagnetic with effective magnetic moments in the range of those expected by the number of unpaired spins of the chromium(III) ion. All melting points are above 100 °C, which prevents us from calling these compounds "ionic liquids". Nevertheless, they are low for salts of this constitution and may be useful for molten salt reactions. Cyclic voltammetry measurements show no reversible electron-transfer steps. PMID:25531243

Peppel, Tim; Thiele, Philipp; Tang, Mei-Bo; Zhao, Jing-Tai; Köckerling, Martin

2015-02-01

142

Rational design, synthesis and structure-activity relationships of 4-alkoxy- and 4-acyloxy-phenylethylenethiosemicarbazone analogues as novel tyrosinase inhibitors.  

PubMed

In continuing our program aimed to search for potent compounds as highly efficient tyrosinase inhibitors, here a series of novel 4-alkoxy- and 4-acyloxy-phenylethylenethiosemicarbazone analogues were designed, synthesized and their biological activities on mushroom tyrosinase were evaluated. Notably, most of compounds displayed remarkable tyrosinase inhibitory activities with IC50 value of lower than 1.0?M. Furthermore, the structure-activity relationships (SARs) were discussed and the inhibition mechanism and the inhibitory kinetics of selected compounds 7k and 8d were also investigated. Taken together, these results suggested that such compounds could serve as the promising candidates for the treatment of tyrosinase-related disorders and further development of such compounds might be of great interest. PMID:25661448

You, Ao; Zhou, Jie; Song, Senchuan; Zhu, Guoxun; Song, Huacan; Yi, Wei

2015-03-01

143

Evaluating the role of syn-thrusting sedimentation and interaction with frictional detachment in the structural evolution of the SW Tarim basin, NW China: Insights from analogue modeling  

NASA Astrophysics Data System (ADS)

The structural evolution of the fold-and-thrust belt in SW Tarim Basin, NW China is poorly understood as the region is covered by thick Pliocene-Quaternary conglomerate, which significantly decreases the quality of seismic images. We here improve the understanding of the thrust belt evolution with an investigation using analogue modeling on the deformation mechanism based on a case of real geological section, in which we focus on the impact of syn-thrusting sedimentation on the structural style and evolution. The results show that syn-thrusting sedimentation significantly increases the distance and rate of foreland propagation, resulting in a much broader fold-and-thrust belt. The modeling results also suggest that the fold-and-thrust belt exhibits different structural patterns under different syn-thrusting sedimentary conditions. In the case of thick syn-thrusting sediments, a frictional detachment layer of mudstone acts as décollement and the fold-and-thrust belt develops a duplex pattern in the hinterland. In the case of thin syn-thrusting deposits, the belt develops a pop-up structure with backthrusts in the foreland region which cut through the detachment layer. The striking similarity between the model with thick syn-thrusting sediments and the real geologic section implies that the overlying thick Pliocene-Quaternary sediments play a major role in shaping the structure pattern in the fold-and-thrust belt of SW Tarim Basin.

Wang, Chun-yang; Chen, Han-lin; Cheng, Xiao-gan; Li, Kang

2013-11-01

144

Crystal and molecular structure of a series of 15-crown-5-containing styryl heterocycles and their dimethoxy substituted analogues  

SciTech Connect

A comparative study of the molecular geometry and crystal packing of crown-containing styryl heterocycles and their dimethoxy substituted analogues is performed. It is established that all the compounds exhibit an identical type of distortions of the geometry of the central styryl fragment. These are the localization of the {pi}-electron density at the ethylene bond and the bond alternation in a half of the phenyl ring due to the conjugation of lone electron pairs of the oxygen substituents with the chromophore system of the molecule. A comparative analysis of the crystal packings of the compounds reveals extended separate hydrophilic and hydrophobic regions. The hydrophilic regions are built of crown ether fragments, and the hydrophobic regions consist of {pi}-conjugated and aromatic molecular fragments. The hydrophobic regions are characterized by a wide variety of packing motifs, among which stacking packing is absent. For two compounds, the formation of sandwich dimers that are preorganized to enter into the photochemical [2 + 2]cycloaddition reaction is observed.

Kuz'mina, L. G. [Russian Academy of Sciences, Kurnakov Institute of General and Inorganic Chemistry (Russian Federation)], E-mail: kuzmina@igic.ras.ru; Fedorova, O. A.; Andryukhina, E. N.; Mashura, M. M.; Gromov, S. P.; Alfimov, M. V. [Russian Academy of Sciences, Photochemistry Center (Russian Federation)

2006-05-15

145

Natural analogues of nuclear waste glass corrosion.  

SciTech Connect

This report reviews and summarizes studies performed to characterize the products and processes involved in the corrosion of natural glasses. Studies are also reviewed and evaluated on how well the corrosion of natural glasses in natural environments serves as an analogue for the corrosion of high-level radioactive waste glasses in an engineered geologic disposal system. A wide range of natural and experimental corrosion studies has been performed on three major groups of natural glasses: tektite, obsidian, and basalt. Studies of the corrosion of natural glass attempt to characterize both the nature of alteration products and the reaction kinetics. Information available on natural glass was then compared to corresponding information on the corrosion of nuclear waste glasses, specifically to resolve two key questions: (1) whether one or more natural glasses behave similarly to nuclear waste glasses in laboratory tests, and (2) how these similarities can be used to support projections of the long-term corrosion of nuclear waste glasses. The corrosion behavior of basaltic glasses was most similar to that of nuclear waste glasses, but the corrosion of tektite and obsidian glasses involves certain processes that also occur during the corrosion of nuclear waste glasses. The reactions and processes that control basalt glass dissolution are similar to those that are important in nuclear waste glass dissolution. The key reaction of the overall corrosion mechanism is network hydrolysis, which eventually breaks down the glass network structure that remains after the initial ion-exchange and diffusion processes. This review also highlights some unresolved issues related to the application of an analogue approach to predicting long-term behavior of nuclear waste glass corrosion, such as discrepancies between experimental and field-based estimates of kinetic parameters for basaltic glasses.

Abrajano, T.A. Jr.; Ebert, W.L.; Luo, J.S.

1999-01-06

146

Utility of Remote Sensing, Robotic Precursor Data and a Focused Science Hypothesis for a Follow-On Human Exploration Lunar Analogue Mission at the Mistastin Lake (Kamestastin) Impact Structure  

NASA Astrophysics Data System (ADS)

Here we summarize how remote sensing, robotic precursor data and a focused science hypothesis augmented the results from a lunar analogue mission to the Mistastin impact structure in Labrador, Canada. Join me as we go on a magical tour of this crater.

Tornabene, L. L.; Osinski, G. R.; Mader, M. M.; Chanou, A.; Francis, R.; Joliff, B. L.; Marion, C.; McCullough, E.; Pickersgill, A.; Sapers, H.; Souders, K.; Sylvester, P.; Young, K.; Zanetti, M.; Krash Operations; Science Team

2012-03-01

147

The structure of vanin 1: a key enzyme linking metabolic disease and inflammation.  

PubMed

Although part of the coenzyme A pathway, vanin 1 (also known as pantetheinase) sits on the cell surface of many cell types as an ectoenzyme, catalyzing the breakdown of pantetheine to pantothenic acid (vitamin B5) and cysteamine, a strong reducing agent. Vanin 1 was initially discovered as a protein involved in the homing of leukocytes to the thymus. Numerous studies have shown that vanin 1 is involved in inflammation, and more recent studies have shown a key role in metabolic disease. Here, the X-ray crystal structure of human vanin 1 at 2.25?Å resolution is presented, which is the first reported structure from the vanin family, as well as a crystal structure of vanin 1 bound to a specific inhibitor. These structures illuminate how vanin 1 can mediate its biological roles by way of both enzymatic activity and protein-protein interactions. Furthermore, it sheds light on how the enzymatic activity is regulated by a novel allosteric mechanism at a domain interface. PMID:25478849

Boersma, Ykelien L; Newman, Janet; Adams, Timothy E; Cowieson, Nathan; Krippner, Guy; Bozaoglu, Kiymet; Peat, Thomas S

2014-12-01

148

Emulating exhalative chemistry: synthesis and structural characterization of ilinskite, Na[Cu5O2](SeO3)2Cl3, and its K-analogue  

NASA Astrophysics Data System (ADS)

The K- and Na-synthetic analogues of the fumarolic mineral ilinskite have been synthesized by the chemical vapor transport (CVT) reactions method. The A[Cu5O2](SeO3)2Cl3 (A + = K+, Na+) compounds crystallize in the orthorhombic space group Pnma: a = 18.1691(6) Å, b = 6.4483(2) Å, c = 10.5684(4) Å, V = 1238.19(7) Å3, R 1 = 0.018 for 1957 unique reflections with F > 4? F for K[Cu5O2](SeO3)2Cl3 (KI), and a = 17.7489(18) Å, b = 6.4412(6) Å, c = 10.4880(12) Å, V = 1199.0(2) Å3, R 1 = 0.049 for 1300 unique reflections with F > 4? F for Na[Cu5O2](SeO3)2Cl3 (NaI). The crystal structures of KI and NaI are based upon the [O2Cu5]6+ sheets consisting of corner-sharing (OCu4)6+ tetrahedra. The Na-for-K substitution results in the significant expansion of the interlayer space and changes in local coordination of some of the Cu2+ cations. The A + cation coordination changes from fivefold (for Na+) to ninefold (for K+). The CVT reactions method provides a unique opportunity to model physicochemical conditions existing in fumarolic environments and may be used not only to model exhalative processes, but also to predict possible mineral phases that may form in fumaroles. In particular, the K analogue of ilinskite is not known in nature, whereas it may well form from volcanic gases in a K-rich local geochemical environment.

Kovrugin, Vadim M.; Siidra, Oleg I.; Colmont, Marie; Mentré, Olivier; Krivovichev, Sergey V.

2015-02-01

149

Structure at 1.65 A of RhoA and its GTPase-activating protein in complex with a transition-state analogue.  

PubMed

Small G proteins of the Rho family, which includes Rho, Rac and Cdc42Hs, regulate phosphorylation pathways that control a range of biological functions including cytoskeleton formation and cell proliferation. They operate as molecular switches, cycling between the biologically active GTP-bound form and the inactive GDP-bound state. Their rate of hydrolysis of GTP to GDP by virtue of their intrinsic GTPase activity is slow, but can be accelerated by up to 10(5)-fold through interaction with rhoGAP, a GTPase-activating protein that stimulates Rho-family proteins. As such, rhoGAP plays a crucial role in regulating Rho-mediated signalling pathways. Here we report the crystal structure of RhoA and rhoGAP complexed with the transition-state analogue GDP.AlF4- at 1.65 A resolution. There is a rotation of 20 degrees between the Rho and rhoGAP proteins in this complex when compared with the ground-state complex Cdc42Hs.GMPPNP/rhoGAP, in which Cdc42Hs is bound to the non-hydrolysable GTP analogue GMPPNP. Consequently, in the transition state complex but not in the ground state, the rhoGAP domain contributes a residue, Arg85(GAP) directly into the active site of the G protein. We propose that this residue acts to stabilize the transition state of the GTPase reaction. RhoGAP also appears to function by stabilizing several regions of RhoA that are important in signalling the hydrolysis of GTP. PMID:9338791

Rittinger, K; Walker, P A; Eccleston, J F; Smerdon, S J; Gamblin, S J

1997-10-16

150

Synthesis of deoxygalactose-containing sialyl Le(X) ganglioside analogues to elucidate the structure necessary for selectin recognition.  

PubMed

Sialyl Lewis X ganglioside analogues containing 4-deoxy-, 6-deoxy-, and 4,6-dideoxy-D-galactopyranose in place of D-galactopyranose have been synthesized. Glycosylations of 2-(trimethylsilyl)ethyl 2,6-di-O-benzyl-beta-D-galactopyranoside and 2-(trimethylsilyl)ethyl beta-D-fucopyranoside with the phenyl 2-thioglycoside derivative of sialic acid, using N-iodosuccinimide (NIS)-trifluoromethanesulfonic acid (TfOH) as the promoter in acetonitrile, gave the desired 2-(trimethylsilyl)ethyl sialyl-alpha-2-->3)-beta-D-galactopyranoside and -beta-D-fucopyranoside, respectively. The sialylgalactose derivative obtained was then modified to 4-deoxy and 4,6-dideoxy derivatives. These were converted, by O-benzoylation, transformation of the 2-(trimethylsilyl)ethyl group to trichloroacetimidates, and introduction of the methylthio group with methylthiomethylsilane, into the corresponding glycosyl donors, which were then coupled with 2-(trimethylsilyl)ethyl O-(2,3,4-tri-O-benzyl-alpha-L-fucopyranosyl)-(1->3)-O-(2-acetamido-6-O- benzyl-2-deoxy-beta-D-glucopyranosyl)-(1->3)-2,4,6-tri-O-benzyl-beta-D- galactopyranoside in the presence of dimethyl(methylthio)sulfonium triflate (DMTST). The resulting pentasaccharides were each converted to the corresponding alpha-trichloroacetimidates, which, on coupling with (2S, 3R, 4E)-2-azido-3-O-benzoyl-4-octadecene-1,3-diol, gave the desired sphingosine derivatives. Selective reduction of the azide group, N-acylation with octadecanoic acid, O-deacylation, and saponification of the methyl ester afforded the target compounds. PMID:8737249

Komba, S; Ishida, H; Kiso, M; Hasegawa, A

1996-04-01

151

A key factor to the spin parameter of uniformly rotating compact stars: crust structure  

E-print Network

We study the key factor to determine the dimensionless spin parameter $j\\equiv cJ/(GM^2)$ of different kinds of uniformly rotating compact stars, including the traditional neutron stars, hyperonic neutron stars, and hybrid stars, and check the reliability of the results on various types of equations of state of dense matter. The equations of state from the relativistic mean field theory and the MIT bag model are adopted to simulate compact stars. Numerical calculations of rigidly rotating neutron stars are performed using the RNS code in the framework of general relativity by solving the Einstein equations for stationary axis-symmetric spacetime. The crust structure of compact stars is found to be a key factor to determine the maximum value of the spin parameter $j_{\\rm max}$. For the stars with inclusion of the crust, $j_{\\rm max}\\sim 0.7$ is sustained for various kinds of compact stars with $M>0.5 M_{\\odot}$, and is found to be insensitive to the mass of star and selected equations of state. For the traditional neutron stars, hyperonic neutron stars and hybrid stars without crust structure, the value $j_{\\rm max}$ lies in the range of $[0.7, 1.0]$. Thus, not $j>0.7$ but $j>1$ could be treated as the candidate criterion to distinguish the strange quark stars from the other kinds of compact stars. Furthermore, a universal formula $j=0.48(f/f_K)^3-0.42(f/f_K)^2+0.63(f/f_K)$ is suggested to calculate the spin parameter at any rotational frequency for all kinds of compact stars with crust structure and $M>0.5M_{\\odot}$.

B. Qi; N. B. Zhang; B. Y. Sun; S. Y. Wang; J. H. Gao

2014-08-07

152

Ab Initio Conformational Study of Two Lewis X Analogues Gabor I. Csonka*  

E-print Network

similar. 1. Introduction The search for analogues of sialyl Lex (sLex, NeuAc-R-2,3- Gal- -1,4-[Fuc-R-1,2 and the key structural features3 of sLex, required for recognition, were reviewed recently.4 The 2-, 3-, and 4 of sialic acid play essential roles in the E-, P-, and L-selectin recognition of sLex.5 It has been found

Csonka, Gábor István

153

Structure of the key species in the enzymatic oxidation of methane to methanol.  

PubMed

Methane monooxygenase (MMO) catalyses the O2-dependent conversion of methane to methanol in methanotrophic bacteria, thereby preventing the atmospheric egress of approximately one billion tons of this potent greenhouse gas annually. The key reaction cycle intermediate of the soluble form of MMO (sMMO) is termed compound Q (Q). Q contains a unique dinuclear Fe(IV) cluster that reacts with methane to break an exceptionally strong 105 kcal mol(-1) C-H bond and insert one oxygen atom. No other biological oxidant, except that found in the particulate form of MMO, is capable of such catalysis. The structure of Q remains controversial despite numerous spectroscopic, computational and synthetic model studies. A definitive structural assignment can be made from resonance Raman vibrational spectroscopy but, despite efforts over the past two decades, no vibrational spectrum of Q has yet been obtained. Here we report the core structures of Q and the following product complex, compound T, using time-resolved resonance Raman spectroscopy (TR(3)). TR(3) permits fingerprinting of intermediates by their unique vibrational signatures through extended signal averaging for short-lived species. We report unambiguous evidence that Q possesses a bis-?-oxo diamond core structure and show that both bridging oxygens originate from O2. This observation strongly supports a homolytic mechanism for O-O bond cleavage. We also show that T retains a single oxygen atom from O2 as a bridging ligand, while the other oxygen atom is incorporated into the product. Capture of the extreme oxidizing potential of Q is of great contemporary interest for bioremediation and the development of synthetic approaches to methane-based alternative fuels and chemical industry feedstocks. Insight into the formation and reactivity of Q from the structure reported here is an important step towards harnessing this potential. PMID:25607364

Banerjee, Rahul; Proshlyakov, Yegor; Lipscomb, John D; Proshlyakov, Denis A

2015-02-19

154

Survey of Analogue Spacetimes  

NASA Astrophysics Data System (ADS)

Analogue spacetimes (and more boldly, analogue models both of and for gravity), have attracted significant and increasing attention over the last decade and a half. Perhaps the most straightforward physical example, which serves as a template for most of the others, is Bill Unruh's model for a dumb hole,(mute black hole, acoustic black hole), wherein sound is dragged along by a moving fluid—and can even be trapped behind an acoustic horizon. This and related analogue models for curved spacetimes are useful in many ways: analogue spacetimes provide general relativists with extremely concrete physical models to help focus their thinking, and conversely the techniques of curved spacetime can sometimes help improve our understanding of condensed matter and/or optical systems by providing an unexpected and countervailing viewpoint. In this chapter, I shall provide a few simple examples of analogue spacetimes as general background for the rest of the contributions.

Visser, Matt

155

Key Plant Structural and Allocation Traits Depend on Relative Age in the Perennial Herb Pimpinella saxifraga  

PubMed Central

• Background and Aims Perennial plant formations always include a mixture of various-aged individuals of community-creating species, but the physiological and competitive potentials of plants of differing age and the importance on whole community functioning are still not entirely known. The current study tested the hypothesis that ontogenetically old plants have limited biomass investments in leaves and enhanced foliage support costs. • Methods Leaf structure, size and biomass allocation were studied in the perennial herb Pimpinella saxifraga during plant ontogeny from seedling to senile phases to determine age-dependent controls on key plant structural traits. The average duration of the full ontogenetic cycle is approx. 5–10 years in this species. Plants were sampled from shaded and open habitats. • Key Results Leaflet dry mass per unit area (MA) increased, and the fraction of plant biomass in leaflets (FL) decreased with increasing age, leading to a 5- to 11-fold decrease in leaf area ratio (LAR = FL/MA) between seedlings and senescent plants. In contrast, the fraction of below-ground biomass increased with increasing age. Leaflet size and number per leaf increased with increasing age. This was not associated with enhanced support cost in older plants as age-dependent changes in leaf shape and increased foliage packing along the rachis compensated for an overall increase in leaf size. Age-dependent trends were the same in habitats with various irradiance, but the LAR of plants of varying age was approx. 1·5-fold larger in the shade due to lower MA and larger FL. • Conclusions As plant light interception per unit total plant mass scales with LAR, these data demonstrate major age-dependent differences in plant light-harvesting efficiency that are further modified by site light availability. These ontogenetic changes reduce the differences among co-existing species in perennial communities, and therefore need consideration in our understanding of how herbaceous communities function. PMID:15965271

NIINEMETS, ÜLO

2005-01-01

156

Substituent effects of cis-cinnamic acid analogues as plant growh inhibitors.  

PubMed

1-O-cis-Cinnamoyl-?-D-glucopyranose is one of the most potent allelochemicals that has been isolated from Spiraea thunbergii Sieb by Hiradate et al. It derives its strong inhibitory activity from cis-cinnamic acid (cis-CA), which is crucial for phytotoxicity. By preparing and assaying a series of cis-CA analogues, it was previously found that the key features of cis-CA for lettuce root growth inhibition are a phenyl ring, cis-configuration of the alkene moiety, and carboxylic acid. On the basis of a structure-activity relationship study, the substituent effects on the aromatic ring of cis-CA were examined by systematic synthesis and the lettuce root growth inhibition assay of a series of cis-CA analogues having substituents on the aromatic ring. While ortho- and para-substituted analogues exhibited low potency in most cases, meta-substitution was not critical for potency, and analogues having a hydrophobic and sterically small substituent were more likely to be potent. Finally, several cis-CA analogues were found to be more potent root growth inhibitors than cis-CA. PMID:24070619

Nishikawa, Keisuke; Fukuda, Hiroshi; Abe, Masato; Nakanishi, Kazunari; Taniguchi, Tomoya; Nomura, Takashi; Yamaguchi, Chihiro; Hiradate, Syuntaro; Fujii, Yoshiharu; Okuda, Katsuhiro; Shindo, Mitsuru

2013-12-01

157

Structural Analysis of Peptide-Analogues of Human Zona Pellucida ZP1 Protein with Amyloidogenic Properties: Insights into Mammalian Zona Pellucida Formation  

PubMed Central

Zona pellucida (ZP) is an extracellular matrix surrounding and protecting mammalian and fish oocytes, which is responsible for sperm binding. Mammalian ZP consists of three to four glycoproteins, called ZP1, ZP2, ZP3, ZP4. These proteins polymerize into long interconnected filaments, through a common structural unit, known as the ZP domain, which consists of two domains, ZP-N and ZP-C. ZP is related in function to silkmoth chorion and in an evolutionary fashion to the teleostean fish chorion, also fibrous structures protecting the oocyte and embryo, that both have been proven to be functional amyloids. Two peptides were predicted as ‘aggregation-prone’ by our prediction tool, AMYLPRED, from the sequence of the human ZP1-N domain. Here, we present results from transmission electron microscopy, X-ray diffraction, Congo red staining and attenuated total reflectance Fourier-transform infrared spectroscopy (ATR FT-IR), of two synthetic peptide-analogues of these predicted ‘aggregation-prone’ parts of the human ZP1-N domain, that we consider crucial for ZP protein polymerization, showing that they both self-assemble into amyloid-like fibrils. Based on our experimental data, we propose that human ZP (hZP) might be considered as a novel, putative, natural protective amyloid, in close analogy to silkmoth and teleostean fish chorions. Experiments are in progress to verify this proposal. We also attempt to provide insights into ZP formation, proposing a possible model for hZP1-N domain polymerization. PMID:24069181

Louros, Nikolaos N.; Iconomidou, Vassiliki A.; Giannelou, Polina; Hamodrakas, Stavros J.

2013-01-01

158

Structures of the hydrolase domain of zebrafish 10-formyltetrahydrofolate dehydrogenase and its complexes reveal a complete set of key residues for hydrolysis and product inhibition.  

PubMed

10-Formyltetrahydrofolate dehydrogenase (FDH), which is composed of a small N-terminal domain (Nt-FDH) and a large C-terminal domain, is an abundant folate enzyme in the liver and converts 10-formyltetrahydrofolate (10-FTHF) to tetrahydrofolate (THF) and CO2. Nt-FDH alone possesses a hydrolase activity, which converts 10-FTHF to THF and formate in the presence of ?-mercaptoethanol. To elucidate the catalytic mechanism of Nt-FDH, crystal structures of apo-form zNt-FDH from zebrafish and its complexes with the substrate analogue 10-formyl-5,8-dideazafolate (10-FDDF) and with the products THF and formate have been determined. The structures reveal that the conformations of three loops (residues 86-90, 135-143 and 200-203) are altered upon ligand (10-FDDF or THF) binding in the active site. The orientations and geometries of key residues, including Phe89, His106, Arg114, Asp142 and Tyr200, are adjusted for substrate binding and product release during catalysis. Among them, Tyr200 is especially crucial for product release. An additional potential THF binding site is identified in the cavity between two zNt-FDH molecules, which might contribute to the properties of product inhibition and THF storage reported for FDH. Together with mutagenesis studies and activity assays, the structures of zNt-FDH and its complexes provide a coherent picture of the active site and a potential THF binding site of zNt-FDH along with the substrate and product specificity, lending new insights into the molecular mechanism underlying the enzymatic properties of Nt-FDH. PMID:25849409

Lin, Chien Chih; Chuankhayan, Phimonphan; Chang, Wen Ni; Kao, Tseng Ting; Guan, Hong Hsiang; Fun, Hoong Kun; Nakagawa, Atsushi; Fu, Tzu Fun; Chen, Chun Jung

2015-04-01

159

Structural style of a compressive wedge with salt and coal shale decollement levels: Analogue and seismic modelling of the Kuqa Thrust Belt (North Tarim, China)  

NASA Astrophysics Data System (ADS)

The Kuqa foreland fold and thrust belt developed at the contact between the uplifted basement block of the Tien Shan and the Tarim basin in foreland setting, since early Oligocene. It is mainly controlled by two major decollement levels. Thin skin deformation and Mesozoic thrust sheet develop above the Triassic and Jurassic coal and shale layers. The Paleogene and Neogene salt ridges and synclines developed above the stacked thrust sheets through the Paleogene salt layer. 4D Analogue models imaged with X-ray tomography are used to analyse the relative importance several parameters such as (1) the kinematic boundary conditions, (2) the rheological behaviour of the main decollement levels, and (3) erosion and sedimentation, on the present structure evolution. The experiments demonstrate that the geometry of the belt is controlled by the regional distribution of both decollement levels. The lower decollement requires a weak frictional behaviour, pinching toward the south, whereas the viscous Paleogene salt layer, pinching regularly to the South and passing gradually to clastic deposits to the North close to the Tien Shan boundary. The geometry of salt ridges and diapirs dvlopped during the early tectonic phase associated with a low sedimentation rate controls the shape and localisation of the future foreland synclines and boundaries. The synclines grow during the late stage of evolution with a rapid increase in flexure and sedimentation rate. The backstop geometry is the second major element, controlling the dip of the Mesozoic stacked thrust sheet below the salt. Inverted basement block associated to a basement short cut emplaced during the late stage of evolution are both needed to generate the overall geometry of these units. Based on the analogue models, the geometry of the thrust sheet and foreland syncline is used to perform a synthetic seismic profile in order to test the ability to image the deep parts of the thrust sheets below complex structures. The recovered seismic data demonstrate that the sub-thrust sheet could not be well imaged considering the well velocity data and realistic geometry as deduced from surface seismic data.

Callot, Jean Paul; Guichong, Wang; Moretti, Isabelle; Yongxing, Gu; Letouzey, Jean; Wu, Shengyu

2013-04-01

160

STRUCTURE-ACTIVITY STUDY OF PARACETAMOL ANALOGUES: INHIBITION OF REPLICATIVE DNA SYNTHESIS IN V79 CHINESE HAMSTER CELLS  

EPA Science Inventory

Experimental and theoretical evidence pertaining to cytotoxic and genotoxic activity of paracetamol in biological systems was used to formulate a simple mechanistic hypothesis to explain the relative inhibition of replicative DNA synthesis by a series of 19 structurally similar p...

161

Structure–activity relationships of tyrosinase inhibitory combinatorial library of 2,5-disubstituted-1,3,4-oxadiazole analogues  

Microsoft Academic Search

Here the tyrosinase inhibition studies of library of 2,5-disubstituted-1,3,4-oxadiazoles have been reported and their structure–activity relationship (SAR) also have been discussed. The library of the oxadiazoles was synthesized under the microwave irradiation and was structures of these were characterized by different spectral techniques. From this study it could be concluded that for a better inhibition of tyrosinase, electronegative substitution is

Mahmud Tareq Hassan Khan; Muhammad Iqbal Choudhary; Khalid Mohammed Khan; Mubeen Rani; Atta-ur-Rahman

2005-01-01

162

Modification of the structure of a metallopeptide: synthesis and biological evaluation of (111)In-labeled DOTA-conjugated rhenium-cyclized alpha-MSH analogues.  

PubMed

Rhenium-cyclized CCMSH analogues are novel melanoma-targeting metallopeptides with high tumor uptake, long tumor retention, and low background in normal tissues, which make these metallopeptides an ideal structural motif for designing novel melanoma-targeting agents. ReCCMSH has been derivatized with a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelate so that it can be labeled with a wide variety of radionuclides for imaging and therapeutic applications. This study involved optimization of the in vivo biological properties of DOTA-ReCCMSH (S), through modification of the structure of the metallopeptide. Several DOTA-ReCCMSH analogues, Ac-Lys(DOTA)-ReCCMSH (4) DOTA-ReCCMSH(Arg(11)) (6), DOTA-ReCCMSH-OH (8), and DOTA-ReCCMSH-Asp-OH (10), were synthesized using solid phase peptide synthesis followed by rhenium cyclization. The IC(50) values of the metallopeptides were determined through competitive binding assays against (125)I-(Tyr(2))-NDP. Radiolabeling of the DOTA-rhenium-cyclized peptides with (111)In was carried out in NH(4)OAc (0.1 M; pH 5.5)-buffered solution for 30 min at 70 degrees C. The stability of the radiolabeled complexes was evaluated in 0.01 M, pH 7.4, phosphate-buffered saline/0.1% bovine serum albumin solution. After separation of the radiolabeled peptide from the unlabeled peptide by reverse phase high-performance liquid chromatography, the biodistribution of the radiolabeled complex was performed in C57 mice bearing B16/F1 murine melanoma tumors. All radiolabeled complexes showed fast blood clearance (2 h postinjection (pi): (111)In-S, 0.07 +/- 0.03% ID/g; (111)In-4, 0.09 +/- 0.06% ID/g; (111)In-6, 0.21 +/- 0.08% ID/g; (111)In-8, 0.11 +/- 0.10% ID/g; and (111)In-10, 0.05 +/- 0.03% ID/g), and their clearance was predominantly through the urine (4 h pi: 93.5 +/- 1.7, 87.8 +/- 6.5, 89.8 +/- 4.2, 93.3 +/- 1.1, and 93.8 +/- 1.8 (% ID) for (111)In-labeled S, 4, 6, 8, and 10, respectively). Tumor uptake values of 9.45 +/- 0.90, 6.01 +/- 2.36, 17.41 +/- 5.61, 9.27 +/- 0.68, and 7.32 +/- 2.09 (% ID/g) for (111)In-labeled S, 4, 6, 8, and 10, respectively, were observed at 4 h pi. The kidney uptake was 9.27 +/- 2.65% ID/g for (111)In-S, 19.02 +/- 2.63% ID/g for (111)In-4, 7.37 +/- 1.13% ID/g for (111)In-6, 8.70 +/- 0.88% ID/g for (111)In-8, and 8.13 +/- 1.47% ID/g for (111)In-10 at 4 h pi. Complex 6 showed high melanoma uptake and lower kidney uptake than the corresponding Lys(11) analogues, supporting 6 for further investigations as a potential therapeutic radiopharmaceutical. PMID:12086490

Cheng, Zhen; Chen, Jianqing; Miao, Yubin; Owen, Nellie K; Quinn, Thomas P; Jurisson, Silvia S

2002-07-01

163

Nonstationary analogue black holes  

E-print Network

We study the existence of analogue nonstationary spherically symmetric black holes. The prime example is the acoustic model (cf. [V], [U]). We consider also a more general class of metrics that could be useful in other physical models of analogue black and white holes. We give examples of the appearance of black holes and of disappearance of white holes. We also discuss the relation between the apparent and the event horizons for the case of analogue black holes. In the end we study the inverse problem of determination of black or white holes by boundary measurements for the spherically symmetric nonstationary metrics.

Gregory Eskin

2014-11-26

164

New Kagome metal Sc?Mn?Al?Si? and its gallium-doped analogues: synthesis, crystal structure, and physical properties.  

PubMed

We report the synthesis, crystal structure, and basic properties of the new intermetallic compound Sc3Mn3Al7Si5. The structure of the compound was established by single-crystal X-ray diffraction, and it crystallizes with a hexagonal structure (Sc3Ni11Si4 type) with Mn atoms forming the Kagome nets. The dc magnetic susceptibility measurements reveal a Curie-Weiss moment of ~0.51 ?(B)/Mn; however, no magnetic order is found for temperatures as low as 1.8 K. Electrical resistivity and heat capacity measurements show that this compound is definitively metallic, with a relatively large specific heat Sommerfeld coefficient, indicating strong electronic correlations. Intriguingly, these features have revealed Sc3Mn3Al7Si5 as a possible quantum spin liquid. With chemical and lattice disorder introduced by doping, a spin liquid to spin glass transition is observed in the highest Ga-doped compounds. The roles of the geometrically frustrated structure and Mn-ligand hybridization in the magnetism of the title compounds are also discussed. PMID:25144523

He, Hua; Miiller, Wojciech; Aronson, Meigan C

2014-09-01

165

Augmenting the activity of antifungal agents against aspergilli using structural analogues of benzoic acid as chemosensitizing agents  

Technology Transfer Automated Retrieval System (TEKTRAN)

Several benzoic acid analogs showed antifungal activity against strains of Aspergillus flavus, A. fumigatus and A. terreus, causative agents of human aspergillosis. Structure-activity analysis revealed that antifungal activities of benzoic and gallic acids increased by addition of a methyl, methoxyl...

166

Augmenting the activity of antifungal agents against aspergilli using structural analogues of benzoic acid as chemosensitizing agents  

Technology Transfer Automated Retrieval System (TEKTRAN)

Structure-activity analysis revealed that antifungal activities of benzoic and gallic acids were increased against strains of Aspergillus flavus, A. fumigatus and A. terreus, causative agents of human aspergillosis, by addition of a methyl, methoxyl or a chloro group at position 4 of the aromatic ri...

167

The crystal structures at 80 K and IR spectra of the complex of 4-methylpyridine with pentachlorophenol and its deuterated analogue  

NASA Astrophysics Data System (ADS)

The crystal structures of the complex of 4-methylpyridine with pentachlorophenol (MP?PCP) and its deuterated analogue (MP?PCP- d) were determined at 80 K by X-ray diffraction. The MP?PCP complex crystallizes in the space group P 1¯ with a = 7.267(7), b = 8.966(9), c = 13.110(14) Å, ? = 99.70(8), ? = 118.16(9), ? = 103.38(8)° and Z = 2 and the MP?PCP- d complex in the monoclinic Cc space group with a = 3.826(2), b = 27.54(2), c = 13.209(12) Å, ? = 101.38(9)° and Z = 4. The O…H…N bridge bond distance of 2.515(4) Å is significantly shorter than that determined at room temperature (2.552(4) Å) and the O?D…N bond length of 2.628(6) Å is only slightly shorter than at room temperature (2.638(3) Å). The temperature dependence of the IR spectra confirms the symmetrization of the OHN hydrogen bond.

Malarski, Z.; Majerz, I.; Lis, T.

1996-07-01

168

Synthesis of the reported structure of piperazirum using a nitro-Mannich reaction as the key stereochemical determining step  

PubMed Central

Summary Piperazirum, isolated from Arum palaestinum Boiss, was originally assigned as r-3,c-5-diisobutyl-c-6-isopropylpiperazin-2-one. The reported structure was synthesised diastereoselectively using a key nitro-Mannich reaction to set up the C5/C6 relative stereochemistry. The structure was unambiguously assigned by single crystal X-ray diffraction but the spectroscopic data did not match those reported for the natural product. The structure of the natural product must therefore be revised. PMID:24062836

Kalogirou, Andreas S; Porter, Michael J; Tizzard, Graham J

2013-01-01

169

Structure-activity relationships of 2',5'-oligoadenylate analogue modifications of prostate-specific membrane antigen (PSMA) antagonists.  

PubMed

Prostate-specific membrane antigen (PSMA) is an ideal biomarker for prostate cancer. A previously reported 2-5A conjugate RBI1033 (3) showed binding affinity more than 10 times higher than the parent urea-based compound (S)-2-(3-((S)-5-amino-1-carboxypentyl)ureido) pentanedioic acid (1). The purpose of this work is to further optimize the structure of 3 to identify highly selective ligands of PSMA. It was found that conjugates having 2-5A in their structure showed extraordinary improved binding affinity to PSMA compared with compound 1. Removal of 2-5A significantly reduced its biological activity. The results will provide a path to agents for targeted imaging and treatment of prostate cancer. PMID:22497258

Wang, Xinning; Tian, Haibin; Lee, Zhenghong; Heston, Warren D W

2012-05-01

170

Molecular structure of the nucleoside analogue inosine using DFT methods: Conformational analysis, crystal simulations and possible behaviour  

NASA Astrophysics Data System (ADS)

Five tautomers of the nucleoside inosine were determined and optimized at the MP2 and B3LYP levels of theory. Several correlations were identified. A comprehensive conformational analysis was carried out on the most stable tautomer N1, and the whole conformational parameters (?, ?, ?, ?, ?, ?', P, ?max) were studied as well as the NBO Natural atomic charges. The calculations were carried out with full relaxation of all geometrical parameters. The search located at least 69 stable structures, 3 of which are within a 1 kcal/mol electronic energy range of the global minimum, and 4 conformers are within a 1 kcal/mol Gibbs energy range. A lower reactivity in inosine than in the natural nucleoside guanosine appears in the N1 and N3 nitrogen atoms. The solid state was simulated through a pentamer form and the structural parameters were compared with the X-ray crystal data available. Several general conclusions were emphasized.

Alvarez-Ros, M. C.; Alcolea Palafox, M.

2013-09-01

171

Biological activity in Technosols as a key factor of their structure  

NASA Astrophysics Data System (ADS)

The studies of the dynamics of organic matters within soils, show that their structural stability depends on the biological activity bound to the degradation of organic products. We wondered what it was for Technosols there. We then tried to specify the contribution of this biological activity to the structure of three contrasted technosols : - Technosol 1: a material originated from a former steel industry containing steel and coke residues, which was deposited two years ago in lysimetric plots - Technosol 2: a constructed soil (30 months) resulting from the combination of paper-mill sludge, thermally treated soil material excavated from a former coking plant site, and green-waste compost - Technosol 3: 30 years old technosol developed on flotation ponds of a former steel mill with strong metallic pollution, on which grows a forest ecosystem If these 3 technosols presented initially a similar organic carbon content (around 70 g.kg-1), the origin of organic matters was different A follow-up of the structural stability of these 3 systems, based on techniques of granulometric soil fractionation and morphological/analytical characterization at ultrastructural scale (TEM/EDX), was realized. Results showed the specific contribution of organic matters to the formation of stable organo-mineral associations, in particular those belonging to (0-50 ?m) fraction. They mainly involved organic matter from vegetal origin coming from the spontaneous colonization of these 3 sites, but also from microbial origin corresponding to rhizospheric bacteria producing exopolymers. Organic matters from the compost and cellulosic fibers from the paper-mill sludge also contributed to the formation of organo-mineral associations all the more that compost was also a source of microorganisms. Organic matters were also associated to pollutant metallic elements (Pb, Zn, Mn) initially brought by the materials, then highlighting their possible transfer and questioning about their (bio)availability. HAP also contributed to the aggregation of technogenic constituents in Technosol 1. The biological activity generated by the presence of exogenous organic matter is thus in short (0-2 years) and mean (30 years) terms, a key factor of the structuration and by there of the pedogenesis of Technosols.

Watteau, Françoise; Villemin, Geneviève; Bouchard, Adeline; Monserié, Marie-France; Séré, Geoffroy; Schwartz, Christophe; Morel, Jean-Louis

2010-05-01

172

Desferrithiocin Analogue Uranium Decorporation Agents  

PubMed Central

Purpose Previous systematic structure-activity studies of the desferrithiocin (DFT) platform have allowed the design and synthesis of analogues and derivatives of DFT that retain the exceptional iron-clearing activity of the parent, while eliminating its adverse effects. We hypothesized that a similar approach could be adopted to identify DFT-related analogues that could effectively decorporate uranium. Materials and Methods The decorporation properties of nine DFT-related analogues were determined in a bile duct-cannulated rat model. Diethylenetriaminepentaacetic acid (DTPA) served as a positive control. Selected ligands also underwent multiple and delayed dosing regimens. Uranium excretion in urine and bile or stool was determined by inductively coupled plasma mass spectroscopy (ICP-MS); tissue levels of uranium were also assessed. Results The two best clinical candidates are (S)-4,5-dihydro-2-[2-hydroxy-4-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(HO)-DADFT-PE (9)], with a 57% reduction in kidney uranium levels on oral (p.o.) administration and (S)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-3'-(HO)-DADFT-PE (10)], with a 62% renal reduction on p.o. administration. The majority of the metal excretion promoted by these analogues is in the bile, thus further reducing kidney actinide exposure. Conclusions While 9 administered p.o. or subcutaneously (s.c.) immediately post-metal is an effective decorporation agent, withholding the dose (s.c.) until 4 h reduced the activity of the compound. Conversion of 9 to its isopropyl ester may circumvent this issue. PMID:19399680

Bergeron, Raymond J.; Wiegand, Jan; Singh, Shailendra

2010-01-01

173

Planetary habitability: lessons learned from terrestrial analogues  

NASA Astrophysics Data System (ADS)

Terrestrial analogue studies underpin almost all planetary missions and their use is essential in the exploration of our Solar system and in assessing the habitability of other worlds. Their value relies on the similarity of the analogue to its target, either in terms of their mineralogical or geochemical context, or current physical or chemical environmental conditions. Such analogue sites offer critical ground-truthing for astrobiological studies on the habitability of different environmental parameter sets, the biological mechanisms for survival in extreme environments and the preservation potential and detectability of biosignatures. The 33 analogue sites discussed in this review have been selected on the basis of their congruence to particular extraterrestrial locations. Terrestrial field sites that have been used most often in the literature, as well as some lesser known ones which require greater study, are incorporated to inform on the astrobiological potential of Venus, Mars, Europa, Enceladus and Titan. For example, the possibility of an aerial habitable zone on Venus has been hypothesized based on studies of life at high-altitudes in the terrestrial atmosphere. We also demonstrate why many different terrestrial analogue sites are required to satisfactorily assess the habitability of the changing environmental conditions throughout Martian history, and recommend particular sites for different epochs or potential niches. Finally, habitable zones within the aqueous environments of the icy moons of Europa and Enceladus and potentially in the hydrocarbon lakes of Titan are discussed and suitable analogue sites proposed. It is clear from this review that a number of terrestrial analogue sites can be applied to multiple planetary bodies, thereby increasing their value for astrobiological exploration. For each analogue site considered here, we summarize the pertinent physiochemical environmental features they offer and critically assess the fidelity with which they emulate their intended target locale. We also outline key issues associated with the existing documentation of analogue research and the constraints this has on the efficiency of discoveries in this field. This review thus highlights the need for a global open access database for planetary analogues.

Preston, Louisa J.; Dartnell, Lewis R.

2014-01-01

174

Binding of a substrate analogue can induce co-operative structure in the plasmin serine-proteinase domain.  

PubMed Central

Human miniplasminogen and miniplasmin were studied by n.m.r. spectroscopy and differential scanning calorimetry (d.s.c.) in order to investigate the structural properties of the serine-proteinase domain. The d.s.c. thermograms of both miniplasminogen and non-inactivated miniplasmin at pH 4.0 can be closely fitted to two transitions, at 62 +/- 2 and 72 +/- 2 degrees C, corresponding to unfolding of the kringle 5 and proteinase domains respectively. No evidence was found, under these conditions, for non-co-operative unfolding of the proteinase domain. On inactivation of miniplasmin with an affinity label, a number of additional resonances arising from residues of the proteinase domain are observed in resolved regions of the n.m.r. spectrum. A combination of variable-temperature n.m.r. and d.s.c. has shown that part of the proteinase domain undergoes a major conformational transition on heating which is distinct from the unfolding of the remainder of the proteinase domain or the kringle 5 domain. This additional transition occurs at a temperature that depends on the nature of the affinity label present and is not observed in the absence of an inactivating agent. These results provide direct evidence for the existence of a region of the proteinase domain which, under these conditions, becomes structured only in the presence of a bound substrate. PMID:8343136

Teuten, A J; Cooper, A; Smith, R A; Dobson, C M

1993-01-01

175

A Mission Control Architecture for robotic lunar sample return as field tested in an analogue deployment to the sudbury impact structure  

NASA Astrophysics Data System (ADS)

A Mission Control Architecture is presented for a Robotic Lunar Sample Return Mission which builds upon the experience of the landed missions of the NASA Mars Exploration Program. This architecture consists of four separate processes working in parallel at Mission Control and achieving buy-in for plans sequentially instead of simultaneously from all members of the team. These four processes were: science processing, science interpretation, planning and mission evaluation. science processing was responsible for creating products from data downlinked from the field and is organized by instrument. Science Interpretation was responsible for determining whether or not science goals are being met and what measurements need to be taken to satisfy these goals. The Planning process, responsible for scheduling and sequencing observations, and the Evaluation process that fostered inter-process communications, reporting and documentation assisted these processes. This organization is advantageous for its flexibility as shown by the ability of the structure to produce plans for the rover every two hours, for the rapidity with which Mission Control team members may be trained and for the relatively small size of each individual team. This architecture was tested in an analogue mission to the Sudbury impact structure from June 6-17, 2011. A rover was used which was capable of developing a network of locations that could be revisited using a teach and repeat method. This allowed the science team to process several different outcrops in parallel, downselecting at each stage to ensure that the samples selected for caching were the most representative of the site. Over the course of 10 days, 18 rock samples were collected from 5 different outcrops, 182 individual field activities - such as roving or acquiring an image mosaic or other data product - were completed within 43 command cycles, and the rover travelled over 2200 m. Data transfer from communications passes were filled to 74%. Sample triage was simulated to allow down-selection to 1 kg of material for return to Earth.

Moores, John E.; Francis, Raymond; Mader, Marianne; Osinski, G. R.; Barfoot, T.; Barry, N.; Basic, G.; Battler, M.; Beauchamp, M.; Blain, S.; Bondy, M.; Capitan, R.-D.; Chanou, A.; Clayton, J.; Cloutis, E.; Daly, M.; Dickinson, C.; Dong, H.; Flemming, R.; Furgale, P.; Gammel, J.; Gharfoor, N.; Hussein, M.; Grieve, R.; Henrys, H.; Jaziobedski, P.; Lambert, A.; Leung, K.; Marion, C.; McCullough, E.; McManus, C.; Neish, C. D.; Ng, H. K.; Ozaruk, A.; Pickersgill, A.; Preston, L. J.; Redman, D.; Sapers, H.; Shankar, B.; Singleton, A.; Souders, K.; Stenning, B.; Stooke, P.; Sylvester, P.; Tornabene, L.

2012-12-01

176

X-ray absorption fine-structure spectroscopy studies of Fe sites in natural human neuromelanin and synthetic analogues.  

PubMed Central

X-ray absorption fine-structure spectroscopy is used to study the local environment of the iron site in natural (human) neuromelanin extracted from substantia nigra tissue and in various synthetic neuromelanins. All the materials show Fe centered in a nearest neighbor sixfold (distorted) oxygen octahedron; the Fe-O distances, while slightly different in the natural and synthetic neuromelanin, are both approximately 2.0 A. Appreciable differences arise, however, in the second (and higher) coordination shells. In this case the synthetic melanin has the four planar oxygens bound to carbon rings with Fe-C distances of approximately 2.82 and 4.13 A; the human sample does not show the 2.82 A link but instead indicates a double shell at approximately 3.45 and 3.78 A. PMID:9826634

Kropf, A J; Bunker, B A; Eisner, M; Moss, S C; Zecca, L; Stroppolo, A; Crippa, P R

1998-01-01

177

Regioselective Domino Metathesis of Unsymmetrical 7-Oxanorbornenes with Electron-Rich Vinyl Acetate toward Biologically Active Glutamate Analogues  

PubMed Central

In this article a regioselective domino metathesis reaction of unsymmetrical 7-oxanorbornenes, readily available by a tandem Ugi/Diels–Alder reaction as a key step, promoted by the Hoveyda–Grubbs second-generation catalyst in the presence of electron-rich vinyl acetate as a cross metathesis (CM) substrate is reported. The mechanism for the unusually high regioselectivity observed in the CM reaction was investigated, and a reaction course where a Fischer-type carbene [“Ru”= CH(OAc)] generates a steric interaction is proposed. The metathesis products were further converted to four artificial glutamate analogues whose structures were inspired by naturally derived excitatory glutamate analogues, dysiherbaine and neodysiherbaine. Interestingly, one of the synthetic analogues (28a) induced a cataleptic state in mice. Further electrophysiological studies suggest that 28a might inhibit excitatory synaptic transmission by a yet unknown indirect pathway. PMID:20485531

Oikawa, Masato; Ikoma, Minoru; Sasaki, Makoto; Gill, Martin B.; Swanson, Geoffrey T.; Shimamoto, Keiko; Sakai, Ryuichi

2010-01-01

178

Structured Codes Improve the Bennett-Brassard-84 Quantum Key Rate  

E-print Network

A central goal in information theory and cryptography is finding simple characterizations of optimal communication rates subject to various restrictions and security requirements. Ideally, the optimal key rate for a quantum key distribution (QKD) protocol would be given by {\\em single-letter formula} involving a simple optimization over a single use of an effective channel. We explore the possibility of such a formula for one of the simplest and most widely used QKD protocols--Bennett-Brassard-84 (BB84) with one way classical post-processing. We show that a conjectured single-letter key-rate formula is false, uncovering a deep ignorance about asymptotically good private codes and pointing towards unfortunate complications in the theory of QKD. These complications are not without benefit--with added complexity comes better key rates than previously thought possible. We improve the threshold for secure key generation from a bit error rate of 0.124 to 0.129.

Graeme Smith; Joseph M. Renes; John A. Smolin

2008-04-28

179

MSI-78, an Analogue of the Magainin Antimicrobial Peptides, Disrupts Lipid Bilayer Structure via Positive Curvature Strain  

PubMed Central

In this work, we present the first characterization of the cell lysing mechanism of MSI-78, an antimicrobial peptide. MSI-78 is an amphipathic ?-helical peptide designed by Genaera Corporation as a synthetic analog to peptides from the magainin family. 31P-NMR of mechanically aligned samples and differential scanning calorimetry (DSC) were used to study peptide-containing lipid bilayers. DSC showed that MSI-78 increased the fluid lamellar to inverted hexagonal phase transition temperature of 1,2-dipalmitoleoyl-phosphatidylethanolamine indicating the peptide induces positive curvature strain in lipid bilayers. 31P-NMR of lipid bilayers composed of MSI-78 and 1-palmitoyl-2-oleoyl-phosphatidylethanolamine demonstrated that the peptide inhibited the fluid lamellar to inverted hexagonal phase transition of 1-palmitoyl-2-oleoyl-phosphatidylethanolamine, supporting the DSC results, and the peptide did not induce the formation of nonlamellar phases, even at very high peptide concentrations (15 mol %). 31P-NMR of samples containing 1-palmitoyl-2-oleoyl-phosphatidylcholine and MSI-78 revealed that MSI-78 induces significant changes in the bilayer structure, particularly at high peptide concentrations. At lower concentrations (1–5%), the peptide altered the morphology of the bilayer in a way consistent with the formation of a toroidal pore. Higher concentrations of peptide (10–15%) led to the formation of a mixture of normal hexagonal phase and lamellar phase lipids. This work shows that MSI-78 induces significant changes in lipid bilayers via positive curvature strain and presents a model consistent with both the observed spectral changes and previously published work. PMID:12719236

Hallock, Kevin J.; Lee, Dong-Kuk; Ramamoorthy, A.

2003-01-01

180

Ultradeep Pyrosequencing and Molecular Modeling Identify Key Structural Features of Hepatitis B Virus RNase H, a Putative Target  

E-print Network

Ultradeep Pyrosequencing and Molecular Modeling Identify Key Structural Features of Hepatitis B, Francea ; National Reference Center for Viral Hepatitis B, C and Delta, Department of Virology, Hôpital of Thessaloniki, Salonika, Greeced ; INSERM U1052, Viral Hepatitis Research Team, Lyon, Francee ; Hepatology

Boyer, Edmond

181

Enhancements of eddy current testing techniques for quantitative nondestructive testing of key structural components of nuclear power plants  

Microsoft Academic Search

In this paper, studies on upgrade of eddy current testing (ECT) techniques for inspection of stress corrosion cracks (SCC) in key structural components of a nuclear power plant are reported. Access and scanning vehicle (robot), advanced probes for steam generator (SG) tube inspection, developments and evaluations of new ECT probes for welding joint, and ECT-based crack sizing technique are described,

Zhenmao Chen; Noritaka Yusa; Kenzo Miya

2008-01-01

182

Mobilizing Communities around HIV Prevention for Youth: How Three Coalitions Applied Key Strategies to Bring about Structural Changes  

ERIC Educational Resources Information Center

Increasingly, HIV prevention efforts must focus on altering features of the social and physical environment to reduce risks associated with HIV acquisition and transmission. Community coalitions provide a vehicle for bringing about sustainable structural changes. This article shares lessons and key strategies regarding how three community…

Chutuape, Kate S.; Willard, Nancy; Sanchez, Kenia; Straub, Diane M.; Ochoa, Tara N.; Howell, Kourtney; Rivera, Carmen; Ramos, Ibrahim; Ellen, Jonathan M.

2010-01-01

183

Structured Codes Improve the Bennett-Brassard-84 Quantum Key Rate  

NASA Astrophysics Data System (ADS)

A central goal in information theory and cryptography is finding simple characterizations of optimal communication rates under various restrictions and security requirements. Ideally, the optimal key rate for a quantum key distribution (QKD) protocol would be given by a single-letter formula involving optimization over a single use of an effective channel. We explore the possibility of such a formula for the simplest and most widely used QKD protocol, Bennnett-Brassard-84 with one-way classical postprocessing. We show that a conjectured single-letter formula is false, uncovering a deep ignorance about good private codes and exposing unfortunate complications in the theory of QKD. These complications are not without benefit—with added complexity comes better key rates than previously thought possible. The threshold for secure key generation improves from a bit error rate of 0.124 to 0.129.

Smith, Graeme; Renes, Joseph M.; Smolin, John A.

2008-05-01

184

Structured codes improve the Bennett-Brassard-84 quantum key rate.  

PubMed

A central goal in information theory and cryptography is finding simple characterizations of optimal communication rates under various restrictions and security requirements. Ideally, the optimal key rate for a quantum key distribution (QKD) protocol would be given by a single-letter formula involving optimization over a single use of an effective channel. We explore the possibility of such a formula for the simplest and most widely used QKD protocol, Bennnett-Brassard-84 with one-way classical postprocessing. We show that a conjectured single-letter formula is false, uncovering a deep ignorance about good private codes and exposing unfortunate complications in the theory of QKD. These complications are not without benefit-with added complexity comes better key rates than previously thought possible. The threshold for secure key generation improves from a bit error rate of 0.124 to 0.129. PMID:18518263

Smith, Graeme; Renes, Joseph M; Smolin, John A

2008-05-01

185

Quantitative comparisons of analogue models of brittle wedge dynamics  

Microsoft Academic Search

Analogue model experiments are widely used to gain insights into the evolution of geological structures. In this study, we present a direct comparison of experimental results of 14 analogue modelling laboratories using prescribed set-ups. A quantitative analysis of the results will document the variability among models and will allow an appraisal of reproducibility and limits of interpretation. This has direct

Guido Schreurs

2010-01-01

186

Novel ?-MSH Peptide Analogues with Broad Spectrum Antimicrobial Activity  

PubMed Central

Previous investigations indicate that ?-melanocyte-stimulating hormone (?-MSH) and certain synthetic analogues of it exert antimicrobial effects against bacteria and yeasts. However, these molecules have weak activity in standard microbiology conditions and this hampers a realistic clinical use. The aim in the present study was to identify novel peptides with broad-spectrum antimicrobial activity in growth medium. To this purpose, the Gly10 residue in the [DNal(2?)-7, Phe-12]-MSH(6–13) sequence was replaced with conventional and unconventional amino acids with different degrees of conformational rigidity. Two derivatives in which Gly10 was replaced by the residues Aic and Cha, respectively, had substantial activity against Candida strains, including C. albicans, C. glabrata, and C. krusei and against gram-positive and gram-negative bacteria. Conformational analysis indicated that the helical structure along residues 8–13 is a key factor in antimicrobial activity. Synthetic analogues of ?-MSH can be valuable agents to treat infections in humans. The structural preferences associated with antimicrobial activity identified in this research can help further development of synthetic melanocortins with enhanced biological activity. PMID:23626703

Auriemma, Luigia; Limatola, Antonio; Di Maro, Salvatore; Merlino, Francesco; Mangoni, Maria Luisa; Luca, Vincenzo; Di Grazia, Antonio; Gatti, Stefano; Campiglia, Pietro; Gomez-Monterrey, Isabel; Novellino, Ettore; Catania, Anna

2013-01-01

187

Synthesis and biological activities of the respiratory chain inhibitor aurachin D and new ring versus chain analogues  

PubMed Central

Summary Aurachins are myxobacterial 3-farnesyl-4(1H)-quinolone derived compounds initially described as respiratory chain inhibitors, more specifically as inhibitors of various cytochrome complexes. They are also known as potent antibiotic compounds. We describe herein the first synthesis of aurachin D through a key Conrad–Limpach reaction. The same strategy was used to reach some ring as opposed to chain analogues, allowing for the description of structure–activity relationships. Biological screening of the analogues showed antiparasitic, cytotoxic, antibacterial and antifungal activities, and depletion of the mitochondrial membrane potential. The strongest activity was found on Plasmodium falciparum with a selectivity index of 345, compared to Vero cells, for the natural product and its geranyl analogue. The loss of mitochondrial membrane potential induced by aurachins in human U-2 OS osteosarcoma cells was studied, showing the best activity for aurachin D and a naphthalene analogue, yet without totally explaining the observed cytotoxic activity of the compounds. Finally, a synthetic entry is given to the complete carboheterocyclic core of aurachin H through the N-oxidation/epoxidation of aurachin D and a shorter chain analogue, followed by subsequent biomimetic cyclization. PMID:23946854

Li, Xu-Wen; Herrmann, Jennifer; Zang, Yi; Grellier, Philippe; Prado, Soizic

2013-01-01

188

Topos Analogues of the KMS State  

E-print Network

We identify the analogues of KMS state in topos theory. Topos KMS states can be viewed as classes of truth objects associated with a measure \\mu^\\rho (in one-to-one correspondence with an original KMS state \\rho) which satisfies topos condition analogues to the ordinary KMS conditions. Topos KMS states can be defined both externally or internally according to whether the automorphism group of geometric morphisms acts externally on the topos structure, or the automorphism group is an object in the topos itself, in which case, it acts internally. We illustrate the formalism by a simple example on the Hilbert space $\\Cl^3$.

Joseph Ben Geloun; Cecilia Flori

2013-03-05

189

Synthesis of diosgenin analogues as potential anti-inflammatory agents.  

PubMed

We herein report the synthesis of diosgenin analogues from commercially available diosgenin as the starting material. The structures of newly synthesised compounds were confirmed by (1)H NMR, (13)C NMR and mass spectrometry. All analogues were evaluated for in-vitro anti-inflammatory profile against LPS-induced inflammation in primary peritoneal macrophages isolated from mice by quantification of pro-inflammatory (TNF-?, IL-6 and IL-1?) cytokines in cell culture supernatant using the ELISA technique followed by in-vitro cytotoxicity study. Among the synthesised analogues, analogue 15 [(E) 26-(3',4',5'-trimethoxybenzylidene)-furost-5en-3?-acetate)] showed significant anti-inflammatory activity by inhibiting LPS-induced pro-inflammatory cytokines in a dose-dependent manner without any cytotoxicity. Efficacy and safety of analogue 15 were further validated in an in-vivo system using LPS-induced sepsis model and acute oral toxicity in mice. Oral administration of analogue 15 inhibited the pro-inflammatory cytokines in serum, attenuated the liver and lung injury and reduced the mortality rate in sepsis mice. Acute oral toxicity study showed that analogue 15 is non-toxic at higher dose in BALB/c mice. Molecular docking study revealed the strong binding affinity of diosgenin analogues to the active site of the pro-inflammatory proteins. These findings suggested that analogue 15 may be a useful therapeutic candidate for the treatment of inflammatory diseases. PMID:24816230

Singh, Monika; Hamid, A A; Maurya, Anil K; Prakash, Om; Khan, Feroz; Kumar, Anant; Aiyelaagbe, O O; Negi, Arvind S; Bawankule, Dnyaneshwar U

2014-09-01

190

Impact melt-bearing breccias of the Mistastin Lake impact structure: A unique planetary analogue for ground-truthing proximal ejecta emplacement  

NASA Astrophysics Data System (ADS)

Impact craters are the dominant geological landform on rocky planetary surfaces; however, relationships between specific craters and their ejecta are typically poorly constrained. With limited planetary samples, scientists look to terrestrial craters as analogues. Impact ejecta is defined here as any target material, regardless of its physical state, that is transported beyond the rim of the transient cavity [1]. The original transient cavity reaches its maximum size during the excavation stage of crater formation, before rim collapse begins in the modification stage [2]. In complex craters, during the modification stage, rocks around the periphery of the bowl-shaped transient crater collapse downward and inward to form a series of terraces along the outer margin of the crater structure [3]. Proximal impact ejecta, can therefore be found on the terraces of the modified rim of a complex crater, interior to the final crater rim [1]. Although typically poorly preserved on Earth due to post-impact erosional processes, impact ejecta have been identified in the terraced rim region of the Mistastin Lake impact structure, located in northern Labrador, Canada (55°53'N; 63°18'W) [4]. The Mistastin Lake impact structure is an intermediate-size, complex crater (28 km apparent crater diameter) formed by a meteorite impact ~36 Ma in crystalline target rocks. The original crater has been differentially eroded; however, a terraced rim and distinct central uplift are still observed [5]. The inner portion of the structure is covered by the Mistastin Lake and the surrounding area is locally covered by soil/glacial deposits and vegetation. Locally, allochthonous impactites overlying fractured target rocks are exposed along the lakeshore and along banks of radially cutting streams. They define a consistent stratigraphy, including, from bottom to top: monomict, lithic breccias, allochthonous polymict lithic breccias, and allochthonous impact melt rocks. Mistastin impact breccias range in matrix content, melt-fragment concentration, and contact relationships with adjacent impactites. Initial findings suggest differing origins for impact melt-bearing breccias from a single impact event. Three examples are highlighted: 1) Impact melt-bearing breccias, on an inner terrace, formed in boundary zones where hot impact melt flowed over cooler, ballistically emplaced polymict impact breccias. 2) Locally, a dyke of impact melt-bearing breccia suggests that this unit originated as hot lithic flow that moved laterally along the ground and then intruded as a fracture fill into target rocks. 3) A m-scale lens of melt-bearing breccia within the middle of a thick, 80m impact melt rock unit situated on an inner terrace, suggests that this lens may have originated from the crater floor and been incorporated into the melt pond during emplacement (i.e. movement of the melt from the crater floor to terrace shelf). In summary, the Mistastin Lake impact structure displays a multiple layered ejecta sequence that is consistent with, and requires, a multi-stage ejecta emplacement model as proposed by [1]. References: [1] Osinski et al. (2011) EPSL (310:167-181. [2] Melosh (1989) Oxford Univ. 245 pp. [3] French B. M. (1998) LPI Contribution 954,120pp. [4] Mader et al. (2011) 42nd LPSC, No.1608. [5] Mader et al. (2013) 43rd LPSC, No. 2517.

Mader, M. M.; Osinski, G. R.

2013-12-01

191

A Bivalent Chromatin Structure Marks Key Developmental Genes in Embryonic Stem Cells  

Microsoft Academic Search

SUMMARY The most highly conserved noncoding ele- ments (HCNEs) in mammalian genomes cluster within regions enriched for genes encoding de- velopmentally important transcription factors (TFs). This suggests that HCNE-rich regions may contain key regulatory controls involved in development. We explored this by examining histone methylation in mouse embryonic stem (ES) cells across 56 large HCNE-rich loci. We identified a specific

Bradley E. Bernstein; Tarjei S. Mikkelsen; Xiaohui Xie; Michael Kamal; Dana J. Huebert; James Cuff; Ben Fry; Alex Meissner; Marius Wernig; Kathrin Plath; Rudolf Jaenisch; Alexandre Wagschal; Robert Feil; Stuart L. Schreiber; Eric S. Lander

2006-01-01

192

Synthetic, semisynthetic and natural analogues of peloruside A.  

PubMed

Peloruside A is a macrocyclic natural product from a New Zealand marine sponge Mycale hentscheli. It has attracted significant attention in the synthetic chemistry, cellular and structural biology communities due to its complex structure and potent anticancer activity. Several natural congeners have since been isolated and synthetic analogues have been prepared. This review describes in detail the published syntheses of peloruside analogues and discusses the structure-activity relationships available to date. PMID:25642465

Brackovic, Amira; Harvey, Joanne E

2015-03-01

193

Sila-substitution of alkyl nitrates: synthesis, structural characterization, and sensitivity studies of highly explosive (nitratomethyl)-, bis(nitratomethyl)-, and tris(nitratomethyl)silanes and their corresponding carbon analogues.  

PubMed

A series of analogous nitratomethyl compounds of carbon and silicon of the formula types Me(3)ElCH(2)ONO(2) (1a/1b), Me(2)El(CH(2)ONO(2))(2) (2a/2b), MeEl(CH(2)ONO(2))(3) (3a/3b), (CH(2))(4)El(CH(2)ONO(2))(2) (4a/4b), and (CH(2))(5)El(CH(2)ONO(2))(2) (5a/5b) were synthesized [El = C (a), Si (b); (CH(2))(4)El = (sila)cyclopentane-1,1-diyl; (CH(2))(5)El = (sila)cyclohexane-1,1-diyl]. All compounds were characterized by using NMR, IR, and Raman spectroscopy and mass spectrometry. In addition, the crystal structures of Me(2)C(CH(2)ONO(2))(2) (2a), (CH(2))(4)C(CH(2)ONO(2))(2) (4a), Me(2)Si(CH(2)ONO(2))(2) (2b), and (CH(2))(5)Si(CH(2)ONO(2))(2) (5b) were determined by single-crystal X-ray diffraction. The gas-phase structures of the C/Si analogues 1a and 1b were determined by electron diffraction and compared with the results of quantum chemical calculations at different levels of theory. The thermal stabilities of the C/Si pairs 1a/1b-5a/5b were investigated by using DSC. In addition, their friction and impact sensitivities were measured with standard BAM methods. The extreme sensitivities of the silicon compounds 1b-5b compared to those of the corresponding carbon analogues 1a-5a were discussed in terms of the structures of the C/Si analogues and possible geminal Si...O interactions. PMID:20433159

Evangelisti, Camilla; Klapötke, Thomas M; Krumm, Burkhard; Nieder, Anian; Berger, Raphael J F; Hayes, Stuart A; Mitzel, Norbert W; Troegel, Dennis; Tacke, Reinhold

2010-06-01

194

Structure–activity relationship of piperine and its synthetic analogues for their inhibitory potentials of rat hepatic microsomal constitutive and inducible cytochrome P450 activities  

Microsoft Academic Search

Inhibitors of drug metabolism have important implications in pharmaco-toxicology and agriculture. We have reported earlier that piperine, a major alkaloid of black and long peppers inhibits both constitutive and inducible cytochrome P450 (CYP)-dependent drug metabolising enzymes. In the present study, an attempt has been made to prepare several novel synthetic analogues so as to relate various modifications in the parent

Surrinder Koul; Jawahir L. Koul; Subhash C. Taneja; Kanaya L. Dhar; Deshvir S. Jamwal; Kuldeep Singh; Rashmeet K. Reen; Jaswant Singh

2000-01-01

195

Quantum Analogue Computing  

E-print Network

We briefly review what a quantum computer is, what it promises to do for us, and why it is so hard to build one. Among the first applications anticipated to bear fruit is quantum simulation of quantum systems. While most quantum computation is an extension of classical digital computation, quantum simulation differs fundamentally in how the data is encoded in the quantum computer. To perform a quantum simulation, the Hilbert space of the system to be simulated is mapped directly onto the Hilbert space of the (logical) qubits in the quantum computer. This type of direct correspondence is how data is encoded in a classical analogue computer. There is no binary encoding, and increasing precision becomes exponentially costly: an extra bit of precision doubles the size of the computer. This has important consequences for both the precision and error correction requirements of quantum simulation, and significant open questions remain about its practicality. It also means that the quantum version of analogue computers, continuous variable quantum computers (CVQC) becomes an equally efficient architecture for quantum simulation. Lessons from past use of classical analogue computers can help us to build better quantum simulators in future.

Vivien M. Kendon; Kae Nemoto; William J. Munro

2010-01-13

196

Quantum analogue computing.  

PubMed

We briefly review what a quantum computer is, what it promises to do for us and why it is so hard to build one. Among the first applications anticipated to bear fruit is the quantum simulation of quantum systems. While most quantum computation is an extension of classical digital computation, quantum simulation differs fundamentally in how the data are encoded in the quantum computer. To perform a quantum simulation, the Hilbert space of the system to be simulated is mapped directly onto the Hilbert space of the (logical) qubits in the quantum computer. This type of direct correspondence is how data are encoded in a classical analogue computer. There is no binary encoding, and increasing precision becomes exponentially costly: an extra bit of precision doubles the size of the computer. This has important consequences for both the precision and error-correction requirements of quantum simulation, and significant open questions remain about its practicality. It also means that the quantum version of analogue computers, continuous-variable quantum computers, becomes an equally efficient architecture for quantum simulation. Lessons from past use of classical analogue computers can help us to build better quantum simulators in future. PMID:20603371

Kendon, Vivien M; Nemoto, Kae; Munro, William J

2010-08-13

197

A comparison of the solvation thermodynamics of amino acid analogues in water, 1-octanol and 1-n-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ionic liquids by molecular simulation  

NASA Astrophysics Data System (ADS)

A computational approach is developed to quantitatively study the solvation thermodynamics of amino acid analogues in ionic liquids via molecular simulation. The solvation thermodynamics of amino acid analogues in ionic liquids is important for an understanding of protein-ionic liquid interactions, shedding insight into the structure and solubility of proteins, and the activity of enzymes in ionic liquids. This information is additionally key to developing novel extraction processes. As a result of the challenge of quantitatively describing the solvation behavior of ionic liquids, a key outcome of the present study is the development of a "hydrophobicity" scale to quantitatively describe the amino acid analogues. The scale allows one to separate the results of both the hydrophobic and hydrophillic analogues, simplifying an understanding of the observed trends. Equipped with the proposed hydrophobicity scale, one needs only perform conventional solvation free energy calculations of the amino acid analogues in the ionic liquids of interest. The necessary simulation tools are available in most open-source simulation software, facilitating the adoption of this approach by the simulation community at large. We have studied the case of varying the cation alkyl-chain length of a 1-n-alkyl-3-methylimidazolium cation paired with the bis(trifluoromethylsulfonyl)imide anion. The findings suggest that a judicious selection of both the cation and anion could potentially lead to a solvent for which the amino acid analogues have an affinity far greater than that for both water and a non-polar reference solvent.

Paluch, Andrew S.; Vitter, Cameron A.; Shah, Jindal K.; Maginn, Edward J.

2012-11-01

198

Mycobacterium tuberculosis Glucosyl-3-Phosphoglycerate Synthase: Structure of a Key Enzyme in Methylglucose Lipopolysaccharide Biosynthesis  

PubMed Central

Tuberculosis constitutes today a serious threat to human health worldwide, aggravated by the increasing number of identified multi-resistant strains of Mycobacterium tuberculosis, its causative agent, as well as by the lack of development of novel mycobactericidal compounds for the last few decades. The increased resilience of this pathogen is due, to a great extent, to its complex, polysaccharide-rich, and unusually impermeable cell wall. The synthesis of this essential structure is still poorly understood despite the fact that enzymes involved in glycosidic bond synthesis represent more than 1% of all M. tuberculosis ORFs identified to date. One of them is GpgS, a retaining glycosyltransferase (GT) with low sequence homology to any other GTs of known structure, which has been identified in two species of mycobacteria and shown to be essential for the survival of M. tuberculosis. To further understand the biochemical properties of M. tuberculosis GpgS, we determined the three-dimensional structure of the apo enzyme, as well as of its ternary complex with UDP and 3-phosphoglycerate, by X-ray crystallography, to a resolution of 2.5 and 2.7 Å, respectively. GpgS, the first enzyme from the newly established GT-81 family to be structurally characterized, displays a dimeric architecture with an overall fold similar to that of other GT-A-type glycosyltransferases. These three-dimensional structures provide a molecular explanation for the enzyme's preference for UDP-containing donor substrates, as well as for its glucose versus mannose discrimination, and uncover the structural determinants for acceptor substrate selectivity. Glycosyltransferases constitute a growing family of enzymes for which structural and mechanistic data urges. The three-dimensional structures of M. tuberculosis GpgS now determined provide such data for a novel enzyme family, clearly establishing the molecular determinants for substrate recognition and catalysis, while providing an experimental scaffold for the structure-based rational design of specific inhibitors, which lay the foundation for the development of novel anti-tuberculosis therapies. PMID:19015727

Pereira, Pedro José Barbosa; Empadinhas, Nuno; Albuquerque, Luciana; Sá-Moura, Bebiana; da Costa, Milton S.; Macedo-Ribeiro, Sandra

2008-01-01

199

Biophysical characterization of recombinant proteins: A key to higher structural genomics success  

PubMed Central

Hundreds of genomes have been successfully sequenced to date, and the data are publicly available. At the same time, the advances in large-scale expression and purification of recombinant proteins have paved the way for structural genomics efforts. Frequently, however, little is known about newly expressed proteins calling for large-scale protein characterization to better understand their biochemical roles and to enable structure–function relationship studies. In the Structural Genomics Consortium (SGC), we have established a platform to characterize large numbers of purified proteins. This includes screening for ligands, enzyme assays, peptide arrays and peptide displacement in a 384-well format. In this review, we describe this platform in more detail and report on how our approach significantly increases the success rate for structure determination. Coupled with high-resolution X-ray crystallography and structure-guided methods, this platform can also be used toward the development of chemical probes through screening families of proteins against a variety of chemical series and focused chemical libraries. PMID:20466062

Vedadi, Masoud; Arrowsmith, Cheryl H.; Allali-Hassani, Abdellah; Senisterra, Guillermo; Wasney, Gregory A.

2010-01-01

200

Millennial climatic fluctuations are key to the structure of last glacial ecosystems.  

PubMed

Whereas fossil evidence indicates extensive treeless vegetation and diverse grazing megafauna in Europe and northern Asia during the last glacial, experiments combining vegetation models and climate models have to-date simulated widespread persistence of trees. Resolving this conflict is key to understanding both last glacial ecosystems and extinction of most of the mega-herbivores. Using a dynamic vegetation model (DVM) we explored the implications of the differing climatic conditions generated by a general circulation model (GCM) in "normal" and "hosing" experiments. Whilst the former approximate interstadial conditions, the latter, designed to mimic Heinrich Events, approximate stadial conditions. The "hosing" experiments gave simulated European vegetation much closer in composition to that inferred from fossil evidence than did the "normal" experiments. Given the short duration of interstadials, and the rate at which forest cover expanded during the late-glacial and early Holocene, our results demonstrate the importance of millennial variability in determining the character of last glacial ecosystems. PMID:23613985

Huntley, Brian; Allen, Judy R M; Collingham, Yvonne C; Hickler, Thomas; Lister, Adrian M; Singarayer, Joy; Stuart, Anthony J; Sykes, Martin T; Valdes, Paul J

2013-01-01

201

Structural Insights into Maize Viviparous14, a Key Enzyme in the Biosynthesis of the Phytohormone Abscisic Acid  

SciTech Connect

The key regulatory step in the biosynthesis of abscisic acid (ABA), a hormone central to the regulation of several important processes in plants, is the oxidative cleavage of the 11,12 double bond of a 9-cis-epoxycarotenoid. The enzyme viviparous14 (VP14) performs this cleavage in maize (Zea mays), making it a target for the rational design of novel chemical agents and genetic modifications that improve plant behavior through the modulation of ABA levels. The structure of VP14, determined to 3.2-{angstrom} resolution, provides both insight into the determinants of regio- and stereospecificity of this enzyme and suggests a possible mechanism for oxidative cleavage. Furthermore, mutagenesis of the distantly related CCD1 of maize shows how the VP14 structure represents a template for all plant carotenoid cleavage dioxygenases (CCDs). In addition, the structure suggests how VP14 associates with the membrane as a way of gaining access to its membrane soluble substrate.

Messing, Simon A.J.; Gabelli, Sandra B.; Echeverria, Ignacia; Vogel, Jonathan T.; Guan, Jiahn Chou; Tan, Bao Cai; Klee, Harry J.; McCarty, Donald R.; Amzel, L. Mario (JHU); (Florida)

2011-09-06

202

Structural Insights into Maize Viviparous14, a Key Enzyme in the Biosynthesis of the Phytohormone Abscisic Acid W  

SciTech Connect

The key regulatory step in the biosynthesis of abscisic acid (ABA), a hormone central to the regulation of several important processes in plants, is the oxidative cleavage of the 11,12 double bond of a 9-cis-epoxycarotenoid. The enzyme viviparous14 (VP14) performs this cleavage in maize (Zea mays), making it a target for the rational design of novel chemical agents and genetic modifications that improve plant behavior through the modulation of ABA levels. The structure of VP14, determined to 3.2-{angstrom} resolution, provides both insight into the determinants of regio- and stereospecificity of this enzyme and suggests a possible mechanism for oxidative cleavage. Furthermore, mutagenesis of the distantly related CCD1 of maize shows how the VP14 structure represents a template for all plant carotenoid cleavage dioxygenases (CCDs). In addition, the structure suggests how VP14 associates with the membrane as a way of gaining access to its membrane soluble substrate.

Messing, S.; Gabelli, S; Echeverria, I; Vogel, J; Guan, J; Tan, B; Klee, H; McCarty, D; Amzela, M

2010-01-01

203

Cell Size as a Key Determinant of Phytoplankton Metabolism and Community Structure  

NASA Astrophysics Data System (ADS)

Phytoplankton size structure controls the trophic organization of planktonic communities and their ability to export biogenic materials toward the ocean's interior. Our understanding of the mechanisms that drive the variability in phytoplankton size structure has been shaped by the assumption that the pace of metabolism decreases allometrically with increasing cell size. However, recent field and laboratory evidence indicates that biomass-specific production and growth rates are similar in both small and large cells but peak at intermediate cell sizes. The maximum nutrient uptake rate scales isometrically with cell volume and superisometrically with the minimum nutrient quota. The unimodal size scaling of phytoplankton growth arises from ataxonomic, size-dependent trade-off processes related to nutrient requirement, acquisition, and use. The superior ability of intermediate-size cells to exploit high nutrient concentrations explains their biomass dominance during blooms. Biogeographic patterns in phytoplankton size structure and growth rate are independent of temperature and driven mainly by changes in resource supply.

Marañón, Emilio

2015-01-01

204

Cell size as a key determinant of phytoplankton metabolism and community structure.  

PubMed

Phytoplankton size structure controls the trophic organization of planktonic communities and their ability to export biogenic materials toward the ocean's interior. Our understanding of the mechanisms that drive the variability in phytoplankton size structure has been shaped by the assumption that the pace of metabolism decreases allometrically with increasing cell size. However, recent field and laboratory evidence indicates that biomass-specific production and growth rates are similar in both small and large cells but peak at intermediate cell sizes. The maximum nutrient uptake rate scales isometrically with cell volume and superisometrically with the minimum nutrient quota. The unimodal size scaling of phytoplankton growth arises from ataxonomic, size-dependent trade-off processes related to nutrient requirement, acquisition, and use. The superior ability of intermediate-size cells to exploit high nutrient concentrations explains their biomass dominance during blooms. Biogeographic patterns in phytoplankton size structure and growth rate are independent of temperature and driven mainly by changes in resource supply. PMID:25062405

Marañón, Emilio

2015-01-01

205

Understanding structure and bonding in early actinide 6d(0)5f0 MX6q (M = Th-Np; X = H, F) complexes in comparison with their transition metal 5d0 analogues.  

PubMed

The relationship between structure and bonding in actinide 6d(0)5f(0) MX(6)(q)() complexes (M = Th, Pa, U, Np; X = H, F; q = -2,-1, 0, +1) has been studied, based on density functional calculations with accurate relativistic actinide pseudopotentials. The detailed comparison of these prototype systems with their 5d(0) transition metal analogues (M = Hf, Ta, W, Re) reveals in detail how the 5f orbitals modify the structural preferences of the actinide complexes relative to the transition metal systems. Natural bond orbital analyses on the hydride complexes indicate that 5f orbital involvement in sigma-bonding favors classical structures based on the octahedron, while d orbital contributions to sigma-bonding favor symmetry lowering. The respective roles of f and d orbitals are reversed in the case of pi-bonding, as shown for the fluoride complexes. PMID:15725014

Straka, Michal; Hrobárik, Peter; Kaupp, Martin

2005-03-01

206

Comparing Religious Education in Canadian and Australian Catholic High Schools: Identifying Some Key Structural Issues  

ERIC Educational Resources Information Center

Religious education (RE) in Catholic high schools in Australia and Canada is compared by examining some of the underlying structural factors that shape the delivery of RE. It is argued that in Canadian Catholic schools RE is diminished by three factors that distinguish it from the Australian experience. These are: the level and history of…

Rymarz, Richard

2013-01-01

207

Measuring Drug Court Structure and OperationsKey Components and Beyond  

Microsoft Academic Search

In the past 20 years, drug courts have become a common part of criminal justice systems’ responses to drug-related crime. However, systematic national research has been limited on how drug courts are specifically organized, limiting the ability of staff at individual programs to compare the structure and operations of their program to those from a nationally representative data set. Therefore,

Matthew Hiller; Steven Belenko; Faye Taxman; Douglas Young; Matthew Perdoni; Christine Saum

2010-01-01

208

Identification of key structural characteristics of Schisandra chinensis lignans involved in P-glycoprotein inhibition.  

PubMed

The aim of the present study was to determine the structural requirements for dibenzocyclooctadiene lignans essential for P-glycoprotein inhibition. Altogether 15 structurally related lignans isolated from Schisandra chinensis or prepared by modification of their backbone were investigated, including three pairs of enantiomers. P-Glycoprotein inhibition was quantified using a doxorubicin accumulation assay in human promyelotic leukemia HL60/MDR cells overexpressing P-glycoprotein. A preliminary quantitative structure-activity relationship analysis revealed three main structural features involved in P-glycoprotein inhibition: a 1,2,3-trimethoxy moiety, a 6-acyloxy group, and the absence of a 7-hydroxy group. The most effective inhibitors, (-)-gomisin N (1) and (+)-deoxyschizandrin [(+)-2], were selected for further evaluation of their effects. Both these lignans restored the cytotoxic effect of doxorubicin in HL60/MDR cells and when combined with a subtoxic concentration of this compound increased the proportion of G2/M cells significantly, which is a usual response to treatment with this anticancer drug. PMID:25302569

Slanina, Ji?í; Páchniková, Gabriela; Carnecká, Martina; Porubová Koubíková, Ludmila; Adámková, Lenka; Humpa, Otakar; Smejkal, Karel; Slaninová, Iva

2014-10-24

209

Smad3 deficiency alters key structural elements of the extracellular matrix and mechanotransduction of wound closure  

PubMed Central

The loss of TGF? or its downstream mediator, Smad3, key players in tissue repair, accelerates closure of incisional wounds in mice. In contrast, we now report that excisional ear wounds in mice lacking Smad3 enlarge compared with wild-type controls resulting from changes in extracellular matrix molecules, which alter the mechanotransduction properties of these wounds. Specifically, levels of elastin and glycosoaminoglycans are increased, collagen fibers are more compactly organized, and matrix modulators like integrins, TGF?1, and matrix metalloproteinases (MMPs) are altered both basally and after wounding in Smad3 knockout mice. Mechanical testing of dorsal skin correlates these changes in matrix composition with functional parameters, specifically an increased elastic modulus, suggesting an imbalance of tissue forces. We propose that the altered mechanical elastic properties translate into a persistent retractile force that is opposed by decreased wound contractile forces contributing to the enlarging ear wound in Smad3 knockout mice. These studies highlight a previously undescribed role for Smad3 in the mechanotransduction of matrix unsupported ear wound closure. PMID:16754864

Arany, Praveen R.; Flanders, Kathleen C.; Kobayashi, Tetsu; Kuo, Catherine K.; Stuelten, Christina; Desai, Kartiki V.; Tuan, Rocky; Rennard, Stephen I.; Roberts, Anita B.

2006-01-01

210

Key structure-activity relationships in the vanadium phosphorus oxide catalyst system  

SciTech Connect

The crystal structure of vanadyl pyrophosphate has been redetermined using single crystals obtained from a near solidified melt of a microcrystalline catalyst sample. Crystals that index as vanadyl pyrophosphate obtained from this melt are variable in color. Crystallographic refinement of the single crystal x-ray diffraction data indicates that structural differences among these materials can be described in terms of crystal defects associated with linear disorder of the vanadium atoms. The importance of the disorder is outlined in the context of its effect on the proposed surface topology parallel to (1,0,0). Models of the surface topology simply and intuitively account for the non-stoichometric surface atomic P/V ratio exhibited by selective catalysts of this phase. These models also point to the possible role of the excess phosphorus in providing site isolation of reactive centers at the surface. 33 refs., 7 figs.

Thompson, M.R. (Pacific Northwest Lab., Richland, WA (USA)); Ebner, J.R. (Monsanto Co., St. Louis, MO (USA))

1990-04-01

211

The Default Mode Network and Related Right Hemisphere Structures may be the Key Substrates of Dementia  

PubMed Central

We have employed structural equation models to explicitly distinguish dementia-relevant variance in cognitive task performance (i.e., d) from the variance that is unrelated to a dementing process (i.e., g?). Together g? and d comprise Spearman’s “g”. Although d represents only a minor fraction of the total variance in cognitive task performance, it is more strongly associated with dementia severity than is g?. In this analysis, we replicate d in a new dataspace, the University of Kansas Brain Aging Project, and associate it specifically with regional grey matter atrophy by voxel-based morphometry of magnetic resonance imaging data. The latent variable d localizes to elements of the default mode network and related structures in the R hemisphere. PMID:22842866

Royall, Donald R.; Palmer, Raymond F.; Vidoni, Eric D.; Honea, Robyn A.; Burns, Jeffrey M.

2012-01-01

212

The mechanism of retroviral integration through X-ray structures of its key intermediates  

PubMed Central

To establish successful infection, a retrovirus must insert a DNA replica of its genome into host cell chromosomal DNA1,2. This process is carried out by the intasome, a nucleoprotein complex comprised of a tetramer of integrase (IN) assembled on the viral DNA ends3,4. The intasome engages chromosomal DNA within a target capture complex to carry out strand transfer, irreversibly joining the viral and cellular DNA molecules. Although several intasome/transpososome structures from the DDE(D) recombinase superfamily were reported4-6, the mechanics of target DNA capture and strand transfer by these enzymes have not been established. Herein, we report crystal structures of the intasome from prototype foamy virus in complex with target DNA, elucidating the pre-integration target DNA capture and post-catalytic strand transfer intermediates of the retroviral integration process. The cleft between IN dimers within the intasome accommodates chromosomal DNA in a severely bent conformation, allowing widely spaced IN active sites to access the scissile phosphodiester bonds. Our results elucidate the structural basis for retroviral DNA integration and moreover provide a framework for the design of INs with altered target sequences. PMID:21068843

Maertens, Goedele N.; Hare, Stephen; Cherepanov, Peter

2010-01-01

213

Longevity and thermo-rheological structure of old lithospheres : key constraints form surface and Moho topography.  

NASA Astrophysics Data System (ADS)

Surface topography and Moho are the most robust observables that have been insufficiently exploited for containing the rheological and thermal structure and hence for understanding the longevity and eventual destruction of cratons and "tectons". Craton longevity has been often explained by their buoyancy and analysed by testing gravitational stability of cratonic mantle "keels" as a function of the hypothesized plate thickness and thermo-rheological structure. Destruction of some cratons (e.g. North China) and data indicating little if no buoyancy of some tectons (e.g., Arabian shield) suggest that buoyancy is not the only factor of their stability, and previous studies show that their mechanical strength is as important as buoyancy. The upper bounds on this strength are provided by flexural studies demonstrating that Te values (equivalent elastic thickness) in cratons are highest in the world and may probably reach 150 km. Yet, the sensitivity of common methods is poor for Te values above 80 km while the lower bounds on the strength and the equivalent elastic thickness of cratons are still matter of debate. How this strength is partitioned between crust and mantle, and which set of rheological parameters pertain, remain major unknowns. We show that smooth low topography and "frozen" heterogeneous crustal structure of cratons represent the missing constraints for understanding of craton longevity. The cratonic crust is characterized by isostatically misbalanced density heterogeneities, suggesting that the lithosphere has to be strong enough to keep them "frozen" through the time without producing major gravitational instabilities and topographic undulations. Hence, to constrain thermo-rheological properties of cratons one should first investigate the stability of their topography and internal structure (constrained from seismic and gravity data). Our thermo-mechanical numerical experiments accounting for free surface boundary condition demonstrate that craton stability cannot be warranted by crustal strength only, and that strong dry olivine mantle rheology and cold thick lithosphere are needed for craton survival. We find fairly robust lower-bound limits on their thermo-rheological structure. In particular, the minimal Te needed for long-term stability of continents (cratons or tectons) is approximately 70 km.

François, Thomas; Burov, Evgueni

2014-05-01

214

The investigation of blind continental earthquake sources through analogue and numerical models  

NASA Astrophysics Data System (ADS)

One of the most challenging topic in earthquake geology is to characterize the seismogenic sources, i.e. the potential causative faults of earthquakes. The main seismogenic layer is located in the upper brittle crust. Nevertheless it does not mean that a fault take up the whole schizosphere: i.e. from the brittle-plastic transition to the surface. Indeed, latest damaging earthquakes were generated by blind or "hidden" faults: 23 Oct. 2011, Van earthquake (Mw 7.1, Turkey); 3 Sep 2010, Darfield earthquake (Mw 7.1, New Zealand); 12 January 2010 Haiti earthquake (Mw 7.0); 6 April 2009 L'Aquila earthquake (Mw 6.3, Italy). Therefore understand how a fault grows and develops is a key question to evaluate the seismogenic potential of an area. Analogue model was used to understand kinematics and geometry of the geological structures since the beginning of the modern geology. On the other hand, numerical model develops much more during the last thirty years. Nowadays we can use these two methods working together providing mutual interactions. In the two-three most recent years we tried to use both numerical and analogue models to investigate the long-term and short-term evolution of a blind normal fault. To do this we improved the Analogue Model Laboratory of the University of Pavia with a laser scanner, a stepper motor and other high resolution tools in order to detect the distribution of the deformation mainly induced by blind faults. The goal of this kind of approach is to mimic the effects of the faults movements in a scaled model. We selected two seismogenic source cases: the causative fault of the 1908 Messina earthquake (Mw 7.1) and that of the 2009 L'Aquila earthquake (Mw 6.3). In the first case we investigate the long term evolution of this structure using a set of analogue models and afterwards a numerical model of our sandbox allow us to investigate stress and strain partitioning. In the second case we performed only an analogue model of short-term evolution of the L'Aquila seismogenic source comparing our result with pre-existing numerical models. In both cases we obtain mutual advantages using together experimental results. We believe that the analogue modelling approach coupled with numerical modelling applied to the study of active faults can provide useful insights to investigate the seismic potential of a structure with important appliances also for the seismic risk assessment.

Bonini, L.; Toscani, G.; Seno, S.

2012-04-01

215

The current structure of key actors involved in research on land and soil degradation  

NASA Astrophysics Data System (ADS)

Land and soil conservation topics, the final mandate of the United Convention to Combat desertification in drylands, have been diagnosed as still suffering from a lack of guidance. On the contrary, climate change and biodiversity issues -the other two big subjects of the Rio Conventions- seem to progress and may benefit from the advice of international panels. Arguably the weakness of policy measures and hence the application of scientific knowledge by land users and stakeholders could be the expression of an inadequate research organization and a lack of ability to channel their findings. In order to better understand the size, breadth and depth of the scientific communities involved in providing advice to this convention and to other bodies, this study explores the corpus of international publications dealing with land and/or with soils. A database of several thousands records including a significant part of the literature published so far was performed using the Web of Science and other socio-economic databases such as FRANCIS and CAIRN. We extracted hidden information using bibliometric methods and data mining applied to these scientific publications to map the key actors (laboratories, teams, institutions) involved in research on land and on soils. Several filters were applied to the databases in combination with the word "desertification". The further use of Tetralogie software merges databases, analyses similarities and differences between keywords, disciplines, authors and regions and identifies obvious clusters. Assessing their commonalities and differences, the visualisation of links and gaps between scientists, organisations, policymakers and other stakeholders is possible. The interpretation of the 'clouds' of disciplines, keywords, and techniques will enhance the understanding of interconnections between them; ultimately this will allow diagnosing some of their strengths and weaknesses. This may help explain why land and soil degradation remains a serious global problem that lacks sufficient attention. We hope that this study will contribute to clarify the scientific landscape at stake to remediate possible weaknesses in the future.

Escadafal, Richard; Barbero, Celia; Exbrayat, Williams; Marques, Maria Jose; Ruiz, Manuel; El Haddadi, Anass; Akhtar-Schuster, Mariam

2013-04-01

216

Analogue-to-Digital and Digital-to-Analogue Conversion.  

ERIC Educational Resources Information Center

Discusses circuits for three-bit and four-bit analogue digital converters and digital analogue converters. These circuits feature slow operating speeds that enable the circuitry to be used to demonstrate the mode of operation using oscilloscopes and signal generators. (DDR)

Gregory, Martin

1997-01-01

217

Mutations in hereditary phosphoglucomutase 1 deficiency map to key regions of enzyme structure and function.  

PubMed

Recent studies have identified phosphoglucomutase 1 (PGM1) deficiency as an inherited metabolic disorder in humans. PGM1 deficiency is classified as both a muscle glycogenosis (type XIV) and a congenital disorder of glycosylation of types I and II. Affected patients show multiple disease phenotypes, reflecting the central role of the enzyme in glucose homeostasis, where it catalyzes the interconversion of glucose 1-phosphate and glucose 6-phosphate. The influence of PGM1 deficiency on protein glycosylation patterns is also widespread, affecting both biosynthesis and processing of glycans and their precursors. To date, 21 different mutations involved in PGM1 deficiency have been identified, including 13 missense mutations resulting in single amino acid changes. Growing clinical interest in PGM1 deficiency prompts a review of the molecular context of these mutations in the three-dimensional structure of the protein. Here the known crystal structure of PGM from rabbit (97 % sequence identity to human) is used to analyze the mutations associated with disease and find that many map to regions with clear significance to enzyme function. In particular, amino acids in and around the active site cleft are frequently involved, including regions responsible for catalysis, binding of the metal ion required for activity, and interactions with the phosphosugar substrate. Several of the known mutations, however, are distant from the active site and appear to manifest their effects indirectly. An understanding of how the different mutations that cause PGM1 deficiency affect enzyme structure and function is foundational to providing clinical prognosis and the development of effective treatment strategies. PMID:25168163

Beamer, Lesa J

2015-03-01

218

Surface topography as key constraint on thermo-rheological structure of cratons  

NASA Astrophysics Data System (ADS)

The question why Archean cratons (i.e., the oldest continental plates such as Canada and Australia) survived for billions of years while the rest of the lithosphere has been reworked for several times is both enigmatic and fundamental for plate tectonics. Craton longetivity has been so far explained by their buoyancy and analysed by testing gravitational stability of hardly detectable cratonic mantle "keels" as a function of a hypothesized plate thickness and thermo-rheological structure. Catastrophic destruction of some cratons suggests that buoyancy is not the only factor of their stability, and previous studies show that their mechanical strength is as important as buoyancy. The upper bounds on their strength are provided by flexural studies demonstrating that Te values (equivalent elastic thickness) in cratons are highest in the world and limited to ~ 150 km. Yet, the lower bounds are still matter of debate, as well as the question how the mechanical strength is partitioned between crust and mantle, and which set of rheological parameters represents this behaviour. We show that primary observed cratonic features - flat topography and "frozen" heterogeneous crustal structure - represent the missing constraints for understanding of craton longevity. The cratonic crust is characterized by huge isostatically misbalanced density heterogeneities, suggesting that the lithosphere has to be strong enough to keep them frozen through the time without producing major gravitational instabilities and topographic undulations. Hence, to constrain thermo-rheological properties of cratons one should first investigate the stability of their topography and internal structure. Our thermo-mechanical numerical experiments accounting for free surface boundary condition notably demonstrate that craton stability cannot be warranted by crustal strength, and that strong dry olivine mantle rheology and cold thick lithosphere (1330°C at ~300 km depth) are needed for craton survival, allowing for discarding weaker, "wetter" or hotter alternatives. Hence, without pretending to explain the whole enigma of cratonic survival, nor to reproduce the evolution of any particular craton, we find fairly robust lower-bound limits on their thermo-rheological structure.

Francois, T.; Burov, E.; Meyer, B.; Agard, P.

2012-04-01

219

Structural insights into key sites of vulnerability on HIV-1 Env and Influenza HA  

PubMed Central

Summary Human immunodeficiency virus-1 (HIV-1) envelope protein (Env) and influenza hemagglutinin (HA) are the surface glycoproteins responsible for viral entry into host cells, the first step in the virus life cycle necessary to initiate infection. These glycoproteins exhibit a high degree of sequence variability and glycosylation, which are used as strategies to escape host immune responses. Nonetheless, antibodies with broadly neutralizing activity against these viruses have been isolated that have managed to overcome these barriers. Here, we review recent advances in the structural characterization of these antibodies with their viral antigens that defines a few sites of vulnerability on these viral spikes. These broadly neutralizing antibodies tend to focus their recognition on the sites of similar function between the two viruses: the receptor binding site and membrane fusion machinery. However, some sites of recognition are unique to the virus neutralized, such as the dense shield of oligomannose carbohydrates on HIV-1 Env. These observations are discussed in the context of structure-based design strategies to aid in vaccine design or development of antivirals. PMID:23046130

Julien, Jean-Philippe; Lee, Peter S.; Wilson, Ian A.

2012-01-01

220

Integrated Analysis of Residue Coevolution and Protein Structures Capture Key Protein Sectors in HIV-1 Proteins  

PubMed Central

HIV type 1 (HIV-1) is characterized by its rapid genetic evolution, leading to challenges in anti-HIV therapy. However, the sequence variations in HIV-1 proteins are not randomly distributed due to a combination of functional constraints and genetic drift. In this study, we examined patterns of sequence variability for evidence of linked sequence changes (termed as coevolution or covariation) in 15 HIV-1 proteins. It shows that the percentage of charged residues in the coevolving residues is significantly higher than that in all the HIV-1 proteins. Most of the coevolving residues are spatially proximal in the protein structures and tend to form relatively compact and independent units in the tertiary structures, termed as “protein sectors”. These protein sectors are closely associated with anti-HIV drug resistance, T cell epitopes, and antibody binding sites. Finally, we explored candidate peptide inhibitors based on the protein sectors. Our results can establish an association between the coevolving residues and molecular functions of HIV-1 proteins, and then provide us with valuable knowledge of pathology of HIV-1 and therapeutics development. PMID:25671429

Zhao, Yuqi; Wang, Yanjie; Gao, Yuedong; Li, Gonghua; Huang, Jingfei

2015-01-01

221

Integrated analysis of residue coevolution and protein structures capture key protein sectors in HIV-1 proteins.  

PubMed

HIV type 1 (HIV-1) is characterized by its rapid genetic evolution, leading to challenges in anti-HIV therapy. However, the sequence variations in HIV-1 proteins are not randomly distributed due to a combination of functional constraints and genetic drift. In this study, we examined patterns of sequence variability for evidence of linked sequence changes (termed as coevolution or covariation) in 15 HIV-1 proteins. It shows that the percentage of charged residues in the coevolving residues is significantly higher than that in all the HIV-1 proteins. Most of the coevolving residues are spatially proximal in the protein structures and tend to form relatively compact and independent units in the tertiary structures, termed as "protein sectors". These protein sectors are closely associated with anti-HIV drug resistance, T cell epitopes, and antibody binding sites. Finally, we explored candidate peptide inhibitors based on the protein sectors. Our results can establish an association between the coevolving residues and molecular functions of HIV-1 proteins, and then provide us with valuable knowledge of pathology of HIV-1 and therapeutics development. PMID:25671429

Zhao, Yuqi; Wang, Yanjie; Gao, Yuedong; Li, Gonghua; Huang, Jingfei

2015-01-01

222

John T. Edsall: his key role in the determination of the structure of proteins.  

PubMed

A letter, written in 1947 by John Edsall, outlined a declared intent to set up an X-ray crystallographic laboratory devoted to the study of crystalline heavy atom derivatives of proteins in an attempt to learn more about their structure. The fundamental idea, to the recipient (B.W.L.) totally new, revolutionary, and wholly contrary to all learned certainties, led to a correspondence, presented here in excerpt. Detailed plans were made for the laboratory to be built in the Department of Physical Chemistry at the Harvard Medical School. The proteins to be studied were reviewed and debated. The work of the laboratory is briefly described. Lack of success, the fatal consequence of a then unknown feature of the protein first chosen for study, is now only recently understood. The history of the Edsall idea and initiative is explored, from its beginnings to its acceptance and exploitation. John Edsall is here recognized as prime proponent and developer of the fundamental idea behind the most powerful and, for more than three decades, the only successful approach to the determination of protein structure. PMID:12646349

Low, Barbara W

2003-01-01

223

Structural and functional conservation of key domains in InsP3 and ryanodine receptors.  

PubMed

Inositol-1,4,5-trisphosphate receptors (InsP(3)Rs) and ryanodine receptors (RyRs) are tetrameric intracellular Ca(2+) channels. In each of these receptor families, the pore, which is formed by carboxy-terminal transmembrane domains, is regulated by signals that are detected by large cytosolic structures. InsP(3)R gating is initiated by InsP(3) binding to the InsP(3)-binding core (IBC, residues 224-604 of InsP(3)R1) and it requires the suppressor domain (SD, residues 1-223 of InsP(3)R1). Here we present structures of the amino-terminal region (NT, residues 1-604) of rat InsP(3)R1 with (3.6?Å) and without (3.0?Å) InsP(3) bound. The arrangement of the three NT domains, SD, IBC-? and IBC-?, identifies two discrete interfaces (? and ?) between the IBC and SD. Similar interfaces occur between equivalent domains (A, B and C) in RyR1 (ref. 9). The orientations of the three domains when docked into a tetrameric structure of InsP(3)R and of the ABC domains docked into RyR are remarkably similar. The importance of the ?-interface for activation of InsP(3)R and RyR is confirmed by mutagenesis and, for RyR, by disease-causing mutations. Binding of InsP(3) causes partial closure of the clam-like IBC, disrupting the ?-interface and pulling the SD towards the IBC. This reorients an exposed SD loop ('hotspot' (HS) loop) that is essential for InsP(3)R activation. The loop is conserved in RyR and includes mutations that are associated with malignant hyperthermia and central core disease. The HS loop interacts with an adjacent NT, suggesting that activation re-arranges inter-subunit interactions. The A domain of RyR functionally replaced the SD in full-length InsP(3)R, and an InsP(3)R in which its C-terminal transmembrane region was replaced by that from RyR1 was gated by InsP(3) and blocked by ryanodine. Activation mechanisms are conserved between InsP(3)R and RyR. Allosteric modulation of two similar domain interfaces within an N-terminal subunit reorients the first domain (SD or A domain), allowing it, through interactions of the second domain of an adjacent subunit (IBC-? or B domain), to gate the pore. PMID:22286060

Seo, Min-Duk; Velamakanni, Saroj; Ishiyama, Noboru; Stathopulos, Peter B; Rossi, Ana M; Khan, Samir A; Dale, Philippa; Li, Congmin; Ames, James B; Ikura, Mitsuhiko; Taylor, Colin W

2012-03-01

224

Tertiary Lymphoid Structure-Associated B Cells are Key Players in Anti-Tumor Immunity  

PubMed Central

It is now admitted that the immune system plays a major role in tumor control. Besides the existence of tumor-specific T cells and B cells, many studies have demonstrated that high numbers of tumor-infiltrating lymphocytes are associated with good clinical outcome. In addition, not only the density but also the organization of tumor-infiltrating immune cells has been shown to determine patient survival. Indeed, more and more studies describe the development within the tumor microenvironment of tertiary lymphoid structures (TLS), whose presence has a positive impact on tumor prognosis. TLS are transient ectopic lymphoid aggregates displaying the same organization and functionality as canonical secondary lymphoid organs, with T-cell-rich and B-cell-rich areas that are sites for the differentiation of effector and memory T cells and B cells. However, factors favoring the emergence of such structures within tumors still need to be fully characterized. In this review, we survey the state of the art of what is known about the general organization, induction, and functionality of TLS during chronic inflammation, and more especially in cancer, with a particular focus on the B-cell compartment. We detail the role played by TLS B cells in anti-tumor immunity, both as antigen-presenting cells and tumor antigen-specific antibody-secreting cells, and raise the question of the capacity of chemotherapeutic and immunotherapeutic agents to induce the development of TLS within tumors. Finally, we explore how to take advantage of our knowledge on TLS B cells to develop new therapeutic tools. PMID:25755654

Germain, Claire; Gnjatic, Sacha; Dieu-Nosjean, Marie-Caroline

2015-01-01

225

Structural heritage as a key factor controlling the South China Sea opening  

NASA Astrophysics Data System (ADS)

Since the Palaeozoic times, the South China Sea area has recorded multiple tectono-thermal events (Indosinian and Yenshanian orogeny) whose influence regarding the formation of the basin remains to be clarified. The aim of this work is to document the vertical movements associated with the extensional tectonic, and to address the issue of the role of the structural inheritance in the context of the opening of an oceanic basin. The work is based on a thermochronological multi-method approach, i.e., U/Pb on zircon and fission tracks on zircon (ZFT) and apatite (AFT). These thermochronological data were then combined with field observations, seismic lines and drill-holes data to perform a reconstruction of the pre-rifting stage of the South China Sea. Dating gives a Triassic to lower Cretaceous age for the emplacement of the Yenshanian granitic arc, which was quickly exhumed during the middle of the Cretaceous. Sample analyses from onland northern margin sediments indicate a range of burial temperatures from 120°C to 250°C. The cretaceous basins, filled with the erosional products of the Yanshanian granites, have been partly recycled within the tertiary basins. Thermochronometers from northern margin samples also attest for a middle-late Eocene cooling event below the 120°C isotherm. Thermochronological results from the Palawan Island, which consists of an inverted cretaceous basin, the Proto South China Sea (PSCS) whose crust has nowadays totally been subducted, show that the source of the sediments is the erosion of the Yanshanian magmatic arc. Finally, a middle-late Miocene cooling event recorded both by Apatite and Zircon attests of a major uplift stage that affected the whole Palawan and Borneo accretionary wedges. The interpretation of seismic and drill-hole data supports a new reconstruction of the SCS pre-rift setting that shows crustal necking zones filled with deep marine deposits, fault-bounded troughs showing thick pre-Tertiary syn-tectonic series and zones of thick crust covered by shallow marine sediments. We propose a step-by-step cartographic reconstruction of the SCS opening that emphasizes a partitioning process along major N-S strike-slip faults, probably corresponding to the on-land continuation of PSCS transform faults. The pre-rift architecture of the crust is characterised by fault-bounded depressions that had trapped Tertiary syn-rift sediments. These depressions delimit areas of thick crust often constituted by intruded Mesozoic granitic plutons on which SCS rifting faults tend to root. This work combining a thermochronological and a structural approach brings fundamental information regarding both the sources of the SCS syn-rift sediments and the pre-rift structures that control both the localisation of the deformation and the distribution of the syn-rift sediments.

Meresse, F.; Savva, D.; Wong, P.; Pubellier, M.; Chamot-Rooke, N.; Steuer, S.; Franke, D.; Sapin, F.; Auxietre, J.

2012-12-01

226

Structural and functional conservation of key domains in InsP[subscript 3] and ryanodine receptors  

SciTech Connect

Inositol-1,4,5-trisphosphate receptors (InsP{sub 3}Rs) and ryanodine receptors (RyRs) are tetrameric intracellular Ca{sup 2+} channels. In each of these receptor families, the pore, which is formed by carboxy-terminal transmembrane domains, is regulated by signals that are detected by large cytosolic structures. InsP{sub 3}R gating is initiated by InsP{sub 3} binding to the InsP{sub 3}-binding core (IBC, residues 224-604 of InsP{sub 3}R1) and it requires the suppressor domain (SD, residues 1-223 of InsP{sub 3}R1). Here we present structures of the amino-terminal region (NT, residues 1-604) of rat InsP{sub 3}R1 with (3.6 {angstrom}) and without (3.0 {angstrom}) InsP{sub 3} bound. The arrangement of the three NT domains, SD, IBC-{beta} and IBC-{alpha}, identifies two discrete interfaces ({alpha} and {beta}) between the IBC and SD. Similar interfaces occur between equivalent domains (A, B and C) in RyR1 (ref. 9). The orientations of the three domains when docked into a tetrameric structure of InsP{sub 3}R and of the ABC domains docked into RyR are remarkably similar. The importance of the {alpha}-interface for activation of InsP{sub 3}R and RyR is confirmed by mutagenesis and, for RyR, by disease-causing mutations. Binding of InsP{sub 3} causes partial closure of the clam-like IBC, disrupting the {beta}-interface and pulling the SD towards the IBC. This reorients an exposed SD loop ('hotspot' (HS) loop) that is essential for InsP{sub 3}R activation. The loop is conserved in RyR and includes mutations that are associated with malignant hyperthermia and central core disease. The HS loop interacts with an adjacent NT, suggesting that activation re-arranges inter-subunit interactions. The A domain of RyR functionally replaced the SD in full-length InsP{sub 3}R, and an InsP{sub 3}R in which its C-terminal transmembrane region was replaced by that from RyR1 was gated by InsP{sub 3} and blocked by ryanodine. Activation mechanisms are conserved between InsP{sub 3}R and RyR. Allosteric modulation of two similar domain interfaces within an N-terminal subunit reorients the first domain (SD or A domain), allowing it, through interactions of the second domain of an adjacent subunit (IBC-{beta} or B domain), to gate the pore.

Seo, Min-Duk; Velamakanni, Saroj; Ishiyama, Noboru; Stathopulos, Peter B.; Rossi, Ana M.; Khan, Samir A.; Dale, Philippa; Li, Congmin; Ames, James B.; Ikura, Mitsuhiko; Taylor, Colin W. (UCD); (Toronto); (Cambridge)

2012-07-11

227

Structurally complex habitats provided by Acropora palmata influence ecosystem processes on a reef in the Florida Keys National Marine Sanctuary  

NASA Astrophysics Data System (ADS)

The disappearance of Acropora palmata from reefs in the Florida Keys National Marine Sanctuary (FKNMS) represents a significant loss in the amount of structurally complex habitat available for reef-associated species. The consequences of such a widespread loss of complex structure on ecosystem processes are still unclear. We sought to determine whether the disappearance of complex structure has adversely affected grazing and invertebrate predation rates on a shallow reef in the FKNMS. Surprisingly, we found grazing rates and invertebrate predation rates were lower in the structurally complex A. palmata branches than on the topographically simple degraded reefs. We attribute these results to high densities of aggressively territorial damselfish, Stegastes planifrons, living within A. palmata. Our study suggests the presence of agonistic damselfish can cause the realized spatial patterns of ecosystem processes to deviate from the expected patterns. Reef ecologists must therefore carefully consider the assemblage of associate fish communities when assessing how the mortality of A. palmata has affected coral reef ecosystem processes.

Lemoine, N. P.; Valentine, J. F.

2012-09-01

228

Polyamine analogues modulate gene expression by inhibiting Lysine-Specific Demethylase 1 (LSD1) and altering chromatin structure in human breast cancer cells  

PubMed Central

Aberrant epigenetic repression of gene expression has been implicated in most cancers, including breast cancer. The nuclear amine oxidase, lysine-specific demethylase 1 (LSD1) has the ability to broadly repress gene expression by removing the activating mono- and di-methylation marks at the lysine 4 residue of histone 3 (H3K4me1 & me2). Additionally, LSD1 is highly expressed in estrogen receptor ? negative (ER?) breast cancer cells. Since epigenetic marks are reversible, they make attractive therapeutic targets. Here we examine the effects of polyamine analogue inhibitors of LSD1 on gene expression, with the goal of targeting LSD1 as a therapeutic modality in the treatment of breast cancer. Exposure of the ER-negative human breast cancer cells, MDA-MB-231, to the LSD1 inhibitors, 2d or PG11144, significantly increases global H3K4me1 and H3K4me2, and alters gene expression. Array analysis indicated that 98 (75 up and 23 down) and 477 (237 up and 240 down) genes changed expression by at least 1.5-fold or greater after treatment with 2d and PG11144, respectively. The expression of twelve up-regulated genes by 2d and fourteen up-regulated genes by PG11144 was validated by quantitative RT-PCR. Quantitative chromatin immunoprecipitation (ChIP) analysis demonstrated that up-regulated gene expression by polyamine analogues is associated with increase of the active histone marks H3K4me1, H3K4me2 and H3K9ac, and decrease of the repressive histone marks H3K9me2 and H3K27me3, in the promoter regions of the relevant target genes. These data indicate that the pharmacologic inhibition of LSD1 can effectively alter gene expression and that this therapeutic strategy has potential. PMID:21805138

Zhu, Qingsong; Huang, Yi; Marton, Laurence J.; Woster, Patrick M.; Davidson, Nancy E.; Casero, Robert A.

2011-01-01

229

Structural re-arrangement and peroxidase activation of cytochrome c by anionic analogues of vitamin E, tocopherol succinate and tocopherol phosphate.  

PubMed

Cytochrome c is a multifunctional hemoprotein in the mitochondrial intermembrane space whereby its participation in electron shuttling between respiratory complexes III and IV is alternative to its role in apoptosis as a peroxidase activated by interaction with cardiolipin (CL), and resulting in selective CL peroxidation. The switch from electron transfer to peroxidase function requires partial unfolding of the protein upon binding of CL, whose specific features combine negative charges of the two phosphate groups with four hydrophobic fatty acid residues. Assuming that other endogenous small molecule ligands with a hydrophobic chain and a negatively charged functionality may activate cytochrome c into a peroxidase, we investigated two hydrophobic anionic analogues of vitamin E, ?-tocopherol succinate (?-TOS) and ?-tocopherol phosphate (?-TOP), as potential inducers of peroxidase activity of cytochrome c. NMR studies and computational modeling indicate that they interact with cytochrome c at similar sites previously proposed for CL. Absorption spectroscopy showed that both analogues effectively disrupt the Fe-S(Met(80)) bond associated with unfolding of cytochrome c. We found that ?-TOS and ?-TOP stimulate peroxidase activity of cytochrome c. Enhanced peroxidase activity was also observed in isolated rat liver mitochondria incubated with ?-TOS and tBOOH. A mitochondria-targeted derivative of TOS, triphenylphosphonium-TOS (mito-VES), was more efficient in inducing H2O2-dependent apoptosis in mouse embryonic cytochrome c(+/+) cells than in cytochrome c(-/-) cells. Essential for execution of the apoptotic program peroxidase activation of cytochrome c by ?-TOS may contribute to its known anti-cancer pharmacological activity. PMID:25278024

Yanamala, Naveena; Kapralov, Alexander A; Djukic, Mirjana; Peterson, Jim; Mao, Gaowei; Klein-Seetharaman, Judith; Stoyanovsky, Detcho A; Stursa, Jan; Neuzil, Jiri; Kagan, Valerian E

2014-11-21

230

Novel analogues of the therapeutic complement inhibitor compstatin with significantly improved affinity and potency1  

PubMed Central

Compstatin is a 13-residue disulfide-bridged peptide that inhibits a key step in the activation of the human complement system. Compstatin and its derivatives have shown great promise for the treatment of many clinical disorders associated with unbalanced complement activity. To obtain more potent compstatin analogues, we have now performed an N-methylation scan of the peptide backbone and amino acid substitutions at position 13. One analogue (Ac-I[CVW(Me)QDW-Sar-AHRC](NMe)I-NH2) displayed a 1,000-fold increase in both potency (IC50=62 nM) and binding affinity for C3b (KD=2.3 nM) over that of the original compstatin. Biophysical analysis using surface plasmon resonance and isothermal titration calorimetry suggests that the improved binding originates from more favorable free conformation and stronger hydrophobic interactions. This study provides a series of significantly improved drug leads for therapeutic applications in complement-related diseases, and offers new insights into the structure-activity relationships of compstatin analogues. PMID:21067811

Qu, Hongchang; Magotti, Paola; Ricklin, Daniel; Wu, Emilia L.; Kourtzelis, Ioannis; Wu, You-Qiang; Kaznessis, Yiannis N.; Lambris, John D.

2010-01-01

231

NASA/ESMD Analogue Mission Plans  

NASA Technical Reports Server (NTRS)

A viewgraph presentation exploring Earth and its analogues is shown. The topics include: 1) ESMD Goals for the Use of Earth Analogues; 2) Stakeholders Summary; 3) Issues with Current Analogue Situation; 4) Current state of Analogues; 5) External Implementation Plan (Second Step); 6) Recent Progress in Utilizing Analogues; 7) Website Layout Example-Home Page; 8) Website Layout Example-Analogue Site; 9) Website Layout Example-Analogue Mission; 10) Objectives of ARDIG Analog Initiatives; 11) Future Plans; 12) Example: Cold-Trap Sample Return; 13) Example: Site Characterization Matrix; 14) Integrated Analogue Studies-Prerequisites for Human Exploration; and 15) Rating Scale Definitions.

Hoffman, Stephen J.

2007-01-01

232

Crystal structure of vitelline membrane outer layer protein I (VMO-I): a folding motif with homologous Greek key structures related by an internal three-fold symmetry.  

PubMed Central

The crystal structure of vitelline membrane outer layer protein I (VMO-I), which is isolated from the vitelline membrane outer layer of hen's eggs, has been determined by the multiple isomorphous replacement method and refined to an R-factor of 18.8% at 2.2 A resolution. The main chain folds into an unusual structure that consists of three beta-sheets forming Greek key motifs, which are related by an internal pseudo three-fold symmetry. The internal portion surrounded by these three beta-sheets is filled with hydrophobic side chains. This conformational feature coincides with three internal repeats in the sequence. Although a similar fold exists in the second domain of delta-endotoxin, there are significant structural differences between the two proteins, with the three-fold symmetry being most regular in VMO-I. Images PMID:8131734

Shimizu, T; Vassylyev, D G; Kido, S; Doi, Y; Morikawa, K

1994-01-01

233

Use of lateral structures to monitor and evaluate degradation of key photovoltaic parameters in an organic bulk heterojunction material  

NASA Astrophysics Data System (ADS)

Charge transport and recombination mechanisms within organic bulk heterojunction (BHJ) systems have been studied using lateral devices to perform in situ potentiometry. We have developed a simplified measurement technique using two types of lateral structures to elicit key charge transport parameters and study the time and process dependence of the carrier mobilities and their ratio. Small geometry lateral devices are used to evaluate the mobility of the slower carrier within the P3HT:PCBM material system. Larger structures with 5 in situ voltage probes are used to construct a simple potential profile of the device channel and accurately determine the carrier mobility ratio. These two measurements enable the calculation of carrier densities and the recombination coefficient. We monitor the change in these parameters as the P3HT:PCBM film degrades in the presence of oxygen and also examine the effect of the solvent additive 1,8-diiodooctane on this degradation mechanism. By exposing ethanol vapor to the BHJ film, we induce traps in the material and monitor the shift in dominant nongeminate recombination mechanism to a more unimolecular type. We are also able to measure the resulting decrease in carrier mobilities due to the presence of dipole-induced traps. Lateral devices are useful material diagnostic structures for studying degradation in BHJ materials.

Danielson, Eric; Ooi, Zi-En; Dodabalapur, Ananth

2014-12-01

234

Key experimental information on intermediate-range atomic structures in amorphous Ge2Sb2Te5 phase change material  

NASA Astrophysics Data System (ADS)

Laser-induced crystalline-amorphous phase change of Ge-Sb-Te alloys is the key mechanism enabling the fast and stable writing/erasing processes in rewritable optical storage devices, such as digital versatile disk (DVD) or blu-ray disk. Although the structural information in the amorphous phase is essential for clarifying this fast process, as well as long lasting stabilities of both the phases, experimental works were mostly limited to the short-range order by x ray absorption fine structure. Here we show both the short and intermediate-range atomic structures of amorphous DVD material, Ge2Sb2Te5 (GST), investigated by a combination of anomalous x ray scattering and reverse Monte Carlo modeling. From the obtained atomic configurations of amorphous GST, we have found that the Sb atoms and half of the Ge atoms play roles in the fast phase change process of order-disorder transition, while the remaining Ge atoms act for the proper activation energy of barriers between the amorphous and crystalline phases.

Hosokawa, Shinya; Pilgrim, Wolf-Christian; Höhle, Astrid; Szubrin, Daniel; Boudet, Nathalie; Bérar, Jean-François; Maruyama, Kenji

2012-04-01

235

Oligonucleotide analogues as modulators of the expression and function of noncoding RNAs (ncRNAs): emerging therapeutics applications.  

PubMed

ncRNAs are emerging as key regulators of physiological and pathological processes and therefore have been identified as pharmacological targets and as markers for some diseases. Oligonucleotide analogues represent so far the most widely employed tool for the modulation of the expression of ncRNAs. In this perspective we briefly describe most of the known classes of ncRNAs and then we discuss the design and the applications of oligonucleotide analogues for their targeting. The effects of modifications of the chemical structure of the oligonucleotides on properties such as the binding affinity toward targets and off targets, and the stability to degradation and their biological effects (when known) are discussed. Examples of molecules currently used in clinical trials are also reported. PMID:25280271

Avitabile, Concetta; Cimmino, Amelia; Romanelli, Alessandra

2014-12-26

236

Analogue Missions on Earth, a New Approach to Prepare Future Missions on the Moon  

NASA Astrophysics Data System (ADS)

Human exploration of the Moon is a target by 2020 with an initial lunar outpost planned in polar regions. Current architectures maintain a capability for sorties to other latitudes for science activities. In the early stages of design of lunar outpost infrastructure and science activity planning, it has been recognized that analogue missions could play a major role in Moon mission design. Analogue missions, as high fidelity simulations of human and robotic surface operations, can help field scientists and engineers develop and test strategies as well as user requirements, as they provide opportunities to groundtruth measurements, and for the team to share understanding of key science needs and key engineering trades. These types of missions also provide direct training in planning science operations, and in team building and communication. The Canadian Space Agency's Exploration Core Program targets the development of technology infrastructure elements in key areas of science, technology and robotics in preparation for its role in the future exploration of the Moon and Mars. Within this Program, Analogue Missions specifically target the operations requirements and lessons learned that will reduce costs and lower the risk of planetary surface missions. Analogue missions are simulations of planetary surface operations that take place at analogue sites on Earth. A terrestrial analogue site resembles in some key way: eg. geomorphologically or geochemically, a surface environment of another planet. An analogue mission can, therefore, be defined as an integrated set of activities that represent (or simulate) entire mission designs or narrowly focus on specific aspects of planned or potential future planetary exploration missions. Within the CSA's Exploration Core Program, Analogue Missions facilitate the maturation of science instruments and mission concepts by integrating ongoing space instrument and technology development programs with science and analogue elements. As well as using analogue missions to meet agency programmatic needs, the Canadian Space Agency encourages scientists and engineers to make use of opportunities presented by analogue missions to further their own research objectives. Specific objectives of Analogue Missions are to (1) foster a multidisciplinary approach to planning, data acquisition, processing and interpretation, calibration of instruments, and telemetry during mission operations; (2) integrate new science with emerging technologies; and (3) develop an expertise on exploration architecture design from projects carried out at terrestrial analogue sites. Within Analogue Missions, teams develop planning tools, use mission-specific software and technology, and communicate results as well as lessons learned during tactical operations. The expertise gained through Analogue Missions will contribute to inform on all aspects of exploration architectures, including planetary mobility requirements and astronaut training.

Lebeuf, Martin

237

New materials for analogue experiments: Preliminary tests of magnetorheological fluids  

NASA Astrophysics Data System (ADS)

New materials and related apparatuses are welcome to advance analogue modelling techniques. In this contribution, we report on a first attempt to use magnetorheological (MR) fluids as analogue materials for simulating the mechanical behavior of mobile décollement layers that change their mechanical properties during deformation. For this purpose, a specific sandbox was designed to include the possibility of quickly applying and removing a magnetic field below a MR fluid layer, in order to induce an instantaneous change from a frictional to a viscous behavior in the basal décollement material. The simulation of gravitational gliding and sediment progradation above a basal mobile shale layer provided results that compare well with analogue models produced with other experimental techniques, and with natural structures like those developed in the Niger delta region. This pilot study thus encourages further research for optimizing the applicability of MR fluids to the analogue simulation of geological processes.

Cavozzi, C.; Storti, F.; Nestola, Y.; Salvi, F.; Davoli, G.

2014-09-01

238

Structure of the Trehalose-6-phosphate Phosphatase from Brugia malayi Reveals Key Design Principles for Anthelmintic Drugs  

PubMed Central

Parasitic nematodes are responsible for devastating illnesses that plague many of the world's poorest populations indigenous to the tropical areas of developing nations. Among these diseases is lymphatic filariasis, a major cause of permanent and long-term disability. Proteins essential to nematodes that do not have mammalian counterparts represent targets for therapeutic inhibitor discovery. One promising target is trehalose-6-phosphate phosphatase (T6PP) from Brugia malayi. In the model nematode Caenorhabditis elegans, T6PP is essential for survival due to the toxic effect(s) of the accumulation of trehalose 6-phosphate. T6PP has also been shown to be essential in Mycobacterium tuberculosis. We determined the X-ray crystal structure of T6PP from B. malayi. The protein structure revealed a stabilizing N-terminal MIT-like domain and a catalytic C-terminal C2B-type HAD phosphatase fold. Structure-guided mutagenesis, combined with kinetic analyses using a designed competitive inhibitor, trehalose 6-sulfate, identified five residues important for binding and catalysis. This structure-function analysis along with computational mapping provided the basis for the proposed model of the T6PP-trehalose 6-phosphate complex. The model indicates a substrate-binding mode wherein shape complementarity and van der Waals interactions drive recognition. The mode of binding is in sharp contrast to the homolog sucrose-6-phosphate phosphatase where extensive hydrogen-bond interactions are made to the substrate. Together these results suggest that high-affinity inhibitors will be bi-dentate, taking advantage of substrate-like binding to the phosphoryl-binding pocket while simultaneously utilizing non-native binding to the trehalose pocket. The conservation of the key residues that enforce the shape of the substrate pocket in T6PP enzymes suggest that development of broad-range anthelmintic and antibacterial therapeutics employing this platform may be possible. PMID:24992307

Farelli, Jeremiah D.; Galvin, Brendan D.; Li, Zhiru; Liu, Chunliang; Aono, Miyuki; Garland, Megan; Hallett, Olivia E.; Causey, Thomas B.; Ali-Reynolds, Alana; Saltzberg, Daniel J.; Carlow, Clotilde K. S.; Dunaway-Mariano, Debra; Allen, Karen N.

2014-01-01

239

Further structurally constrained analogues of cis-(6-benzhydrylpiperidin-3-yl)benzylamine with elucidation of bioactive conformation: discovery of 1,4-diazabicyclo[3.3.1]nonane derivatives and evaluation of their biological properties for the monoamine transporters.  

PubMed

Our structure-activity relationship (SAR) study on piperidine analogues for monoamine transporters led to the development of a series of 3,6-disubstituted piperidine derivatives, structurally constrained versions of flexible piperidine analogues, with preferential affinity for the dopamine transporter (DAT). In our attempt to further rigidify this structure to study influence of rigidity on binding and in vivo activity, we have developed a series of 4,8-disubstituted 1,4-diazabicyclo[3.3.1]nonane derivatives. All synthesized derivatives were tested for their affinity at the DAT, serotonin transporter (SERT), and norepinephrine transporter (NET) in the brain by measuring their potency in competing for the binding of [(3)H]WIN 35, 428, [(3)H]citalopram, and [(3)H]nisoxetine, respectively. Selected compounds were also tested for their ability to inhibit uptake of [(3)H]DA. The SAR study led to the discovery of a potent lead compound (-)-S,S-10c which exhibited high affinity and selectivity for the DAT (IC(50) = 22.5 nM; SERT/DAT = 384 and NET/DAT > 444). It is interesting to note that both (-)-10c and the lead compound from the 3,6-disubstituted series (-)-2 exhibited highest activity in their (S,S) isomer indicating similar requirement of regiospecificity for maximum interaction. Overall, our current SAR results corresponded well with the results from less constrained 3,6-disubstituted versions of these molecules albeit the former class exhibited more stringent requirement in molecular structure for activity. However, the potent compounds in the current series exhibited greater selectivity for the DAT compared to their corresponding lesser constrained 3,6-disubstituted versions indicating an effect of rigidity in selective interaction with the transporter proteins. In an effort to elucidate the bioactive conformational structure of the lead molecules in the current and the 3,6-disubstituted series, a preliminary molecular modeling study was carried out where the most rigid derivative (-)-10c was used as a template structure. Compounds (-)-2 and (-)-10c exhibited stimulant activity in locomotor tests in mice in which (-)-2 exhibited a slower onset and longer duration of action compared to (-)-10c. Both compounds occasioned complete cocaine-like responding in mice trained to discriminate 10 mg/kg ip cocaine from vehicle. PMID:15456254

Kolhatkar, Rohit; Cook, Charles D; Ghorai, Sujit K; Deschamps, Jeffrey; Beardsley, Patrick M; Reith, Maarten E A; Dutta, Aloke K

2004-10-01

240

Making Connections in Math: Activating a Prior Knowledge Analogue Matters for Learning  

ERIC Educational Resources Information Center

This study investigated analogical transfer of conceptual structure from a prior-knowledge domain to support learning in a new domain of mathematics: division by fractions. Before a procedural lesson on division by fractions, fifth and sixth graders practiced with a surface analogue (other operations on fractions) or a structural analogue (whole…

Sidney, Pooja G.; Alibali, Martha W.

2015-01-01

241

En Route to Osmium Analogues of KP1019: Synthesis, Structure, Spectroscopic Properties and Antiproliferative Activity of trans-[OsIVCl4(Hazole)2  

PubMed Central

By controlled Anderson type rearrangement reactions complexes of the general formula trans-[OsIVCl4(Hazole)2], where Hazole = 1H-pyrazole, 2H-indazole, 1H-imidazole, and 1H-benzimidazole, have been synthesized. Note that 2H-indazole tautomer stabilization in trans-[OsIVCl4(2H-indazole)2] is unprecedented in coordination chemistry of indazole. The metal ion in these compounds possesses the same coordination environment as ruthenium(III) in (H2ind)[RuIIICl4(Hind)2], where Hind = 1H-indazole, (KP1019), an investigational anticancer drug in phase I clinical trials. These osmium(IV) complexes are appropriate precursors for the synthesis of osmium(III) analogues of KP1019. In addition the formation of an adduct of trans-[OsIVCl4(Hpz)2] with cucurbit[7]uril is described. The compounds have been comprehensively characterized by elemental analysis, EI and ESI mass spectrometry, spectroscopy (IR, UV–vis, 1D and 2D NMR), cyclic voltammetry, and X-ray crystallography. Their antiproliferative acitivity in the human cancer cell lines CH1 (ovarian carcinoma), A549 (nonsmall cell lung carcinoma), and SW480 (colon carcinoma) is reported. PMID:21739939

2011-01-01

242

Desferrithiocin Analogues and Nephrotoxicity  

PubMed Central

The syntheses of a series of 4?-O-alkylated (S)-4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid and 5?-O-alkylated (S)-4,5-dihydro-2-(2,5-dihydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid ligands are described. Their partition between octanol and water, logPapp, is determined, along with their iron-clearing efficiency (ICE) in both non-iron-overloaded, bile duct-cannulated rodents and in iron-overloaded primates. The ligand-promoted biliary ferrokinetics in rats are described for each of the chelators. Plots of logPapp versus ICE in a rodent model for both the 4?-O-alkylated-2,4-dihydroxy and 5?-O-alkylated-2,5-dihydroxy series produced an inverse parabola plot with r2 values of 0.97 and 0.81, respectively. The plots indicate an optimum logPapp/ICE relationship. Because of the nature of the data spread in the 4?-O-alkylated 2,4-dihydroxy series, it will be used to help assess the origin of nephrotoxicity in desferrithiocin analogues: is toxicity simply related to lipophilicity, ICE, or a combination of these properties? PMID:18788724

Bergeron, Raymond J.; Wiegand, Jan; McManis, James S.; Bharti, Neelam; Singh, Shailendra

2009-01-01

243

Crystal structure of the TRIM25 B30.2 (PRYSPRY) domain: a key component of antiviral signalling.  

PubMed

TRIM (tripartite motif) proteins primarily function as ubiquitin E3 ligases that regulate the innate immune response to infection. TRIM25 [also known as Efp (oestrogen-responsive finger protein)] has been implicated in the regulation of oestrogen receptor ? signalling and in the regulation of innate immune signalling via RIG-I (retinoic acid-inducible gene-I). RIG-I senses cytosolic viral RNA and is subsequently ubiquitinated by TRIM25 at its N-terminal CARDs (caspase recruitment domains), leading to type I interferon production. The interaction with RIG-I is dependent on the TRIM25 B30.2 domain, a protein-interaction domain composed of the PRY and SPRY tandem sequence motifs. In the present study we describe the 1.8 Å crystal structure of the TRIM25 B30.2 domain, which exhibits a typical B30.2/SPRY domain fold comprising two N-terminal ?-helices, thirteen ?-strands arranged into two ?-sheets and loop regions of varying lengths. A comparison with other B30.2/SPRY structures and an analysis of the loop regions identified a putative binding pocket, which is likely to be involved in binding target proteins. This was supported by mutagenesis and functional analyses, which identified two key residues (Asp(488) and Trp(621)) in the TRIM25 B30.2 domain as being critical for binding to the RIG-I CARDs. PMID:24015671

D'Cruz, Akshay A; Kershaw, Nadia J; Chiang, Jessica J; Wang, May K; Nicola, Nicos A; Babon, Jeffrey J; Gack, Michaela U; Nicholson, Sandra E

2013-12-01

244

Antimicrobial activity of resveratrol analogues.  

PubMed

Stilbenes, especially resveratrol and its derivatives, have become famous for their positive effects on a wide range of medical disorders, as indicated by a huge number of published studies. A less investigated area of research is their antimicrobial properties. A series of 13 trans-resveratrol analogues was synthesized via Wittig or Heck reactions, and their antimicrobial activity assessed on two different grapevine pathogens responsible for severe diseases in the vineyard. The entire series, together with resveratrol, was first evaluated on the zoospore mobility and sporulation level of Plasmopara viticola (the oomycete responsible for downy mildew). Stilbenes displayed a spectrum of activity ranging from low to high. Six of them, including the most active ones, were subsequently tested on the development of Botrytis cinerea (fungus responsible for grey mold). The results obtained allowed us to identify the most active stilbenes against both grapevine pathogens, to compare the antimicrobial activity of the evaluated series of stilbenes, and to discuss the relationship between their chemical structure (number and position of methoxy and hydroxy groups) and antimicrobial activity. PMID:24918540

Chalal, Malik; Klinguer, Agnès; Echairi, Abdelwahad; Meunier, Philippe; Vervandier-Fasseur, Dominique; Adrian, Marielle

2014-01-01

245

Structure activity and molecular modeling analyses of ribose- and base-modified uridine 5?-triphosphate analogues at the human P2Y2 and P2Y4 receptors  

PubMed Central

With the long-term goal of developing receptor subtype-selective high affinity agonists for the uracil nucleotide-activated P2Y receptors we have carried out a series of structure activity and molecular modeling studies of the human P2Y2 and P2Y4 receptors. UTP analogues with substitutions in the 2?-position of the ribose moiety retained capacity to activate both P2Y2 and P2Y4 receptors. Certain of these analogues were equieffective for activation of both receptors whereas 2?-amino-2?-deoxy-UTP exhibited higher potency for the P2Y2 receptor and 2?-azido-UTP exhibited higher potency for the P2Y4 receptor. 4-Thio substitution of the uracil base resulted in a UTP analogue with increased potency relative to UTP for activation of both the P2Y2 and P2Y4 receptors. In contrast, 2-thio substitution and halo- or alkyl substitution in the 5-position of the uracil base resulted in molecules that were 3–30-fold more potent at the P2Y2 receptor than P2Y4 receptor. 6-Aza-UTP was a P2Y2 receptor agonist that exhibited no activity at the P2Y4 receptor. Stereoisomers of UTP?S and 2?-deoxy-UTP?S were more potent at the P2Y2 than P2Y4 receptor, and the R-configuration was favored at both receptors. Molecular docking studies revealed that the binding mode of UTP is similar for both the P2Y2 and P2Y4 receptor binding pockets with the most prominent dissimilarities of the two receptors located in the second transmembrane domain (V90 in the P2Y2 receptor and I92 in the P2Y4 receptor) and the second extracellular loop (T182 in the P2Y2 receptor and L184 in the P2Y4 receptor). In summary, this work reveals substitutions in UTP that differentially affect agonist activity at P2Y2 versus P2Y4 receptors and in combination with molecular modeling studies should lead to chemical synthesis of new receptor subtype-selective drugs. PMID:16359641

Jacobson, Kenneth A.; Costanzi, Stefano; Ivanov, Andrei A.; Tchilibon, Susanna; Besada, Pedro; Gao, Zhan-Guo; Maddileti, Savitri; Harden, T. Kendall

2015-01-01

246

Stimulation of Inositol 1,4,5-Trisphosphate (IP3) Receptor Subtypes by Analogues of IP3  

PubMed Central

Most animal cells express mixtures of the three subtypes of inositol 1,4,5-trisphosphate receptor (IP3R) encoded by vertebrate genomes. Activation of each subtype by different agonists has not hitherto been examined in cells expressing defined homogenous populations of IP3R. Here we measure Ca2+ release evoked by synthetic analogues of IP3 using a Ca2+ indicator within the lumen of the endoplasmic reticulum of permeabilized DT40 cells stably expressing single subtypes of mammalian IP3R. Phosphorylation of (1,4,5)IP3 to (1,3,4,5)IP4 reduced potency by ?100-fold. Relative to (1,4,5)IP3, the potencies of IP3 analogues modified at the 1-position (malachite green (1,4,5)IP3), 2-position (2-deoxy(1,4,5)IP3) or 3-position (3-deoxy(1,4,5)IP3, (1,3,4,5)IP4) were similar for each IP3R subtype. The potency of an analogue, (1,4,6)IP3, in which the orientations of the 2- and 3-hydroxyl groups were inverted, was also reduced similarly for all three IP3R subtypes. Most analogues of IP3 interact similarly with the three IP3R subtypes, but the decrease in potency accompanying removal of the 1-phosphate from (1,4,5)IP3 was least for IP3R3. Addition of a large chromophore (malachite green) to the 1-phosphate of (1,4,5)IP3 only modestly reduced potency suggesting that similar analogues could be used to measure (1,4,5)IP3 binding optically. These data provide the first structure-activity analyses of key IP3 analogues using homogenous populations of each mammalian IP3R subtype. They demonstrate broadly similar structure-activity relationships for all mammalian IP3R subtypes and establish the potential utility of (1,4,5)IP3 analogues with chromophores attached to the 1-position. PMID:23372785

Saleem, Huma; Tovey, Stephen C.; Rahman, Taufiq; Riley, Andrew M.; Potter, Barry V. L.; Taylor, Colin W.

2013-01-01

247

Cardiac specific effects of thyroid hormone analogues.  

PubMed

There is significant interest in development of thyroid hormone analogues to harness specific properties as therapeutic agents for a variety of clinical indications including obesity, hypercholesterolemia, heart failure, and thyrotoxicosis. To date, most analogues have been designed to target liver specific effects, which can promote weight loss and lipid lowering through either tissue specific uptake or thyroid hormone receptor (TR) ? isoform selectivity at the same time minimizing the unwanted cardiac and bone effects. We have developed a molecular biomarker assay to study the induction of the transcription of the cardiac specific ?-myosin heavy chain (MHC) gene as a more sensitive and specific measure of thyroid hormone action on cardiac myocytes. We tested 5 TR? and 1 TR? selective agonists as well as 2 putative TR antagonists in our ?-MHC hnRNA assay. Using reverse transcription and polymerase chain reaction, we measured the induction of the ?-MHC primary transcript in response to administration of drug. The TR? and only 2 of the TR? agonists were highly active, when compared to the effect of T3, at the level of the cardiac myocyte. In addition, our data suggests that the reason that the antagonist NH-3 is not able to block the T3-mediated induction of ?-MHC is that it does not get transported into the cardiac myocyte. Our data suggest that this assay will be useful in preclinical studies of the potential cardiac specific effects of thyroid hormone analogues and that predictions of function based on structure are not necessarily accurate or complete. PMID:22009366

Danzi, S; Klein, I

2011-10-01

248

Condensed matter analogues of cosmology  

NASA Astrophysics Data System (ADS)

It is always exciting when developments in one branch of physics turn out to have relevance in a quite different branch. It would be hard to find two branches farther apart in terms of energy scales than early-universe cosmology and low-temperature condensed matter physics. Nevertheless ideas about the formation of topological defects during rapid phase transitions that originated in the context of the very early universe have proved remarkably fruitful when applied to a variety of condensed matter systems. The mathematical frameworks for describing these systems can be very similar. This interconnection has led to a deeper understanding of the phenomena in condensed matter systems utilizing ideas from cosmology. At the same time, one can view these condensed matter analogues as providing, at least in a limited sense, experimental access to the phenomena of the early universe for which no direct probe is possible. As this special issue well illustrates, this remains a dynamic and exciting field. The basic idea is that when a system goes through a rapid symmetry-breaking phase transition from a symmetric phase into one with spontaneously broken symmetry, the order parameter may make different choices in different regions, creating domains that when they meet can trap defects. The scale of those domains, and hence the density of defects, is constrained by the rate at which the system goes through the transition and the speed with which order parameter information propagates. This is what has come to be known as the Kibble-Zurek mechanism. The resultant scaling laws have now been tested in a considerable variety of different systems. The earliest experiments illustrating the analogy between cosmology and condensed matter were in liquid crystals, in particular on the isotropic-to-nematic transition, primarily because it is very easy to induce the phase transition (typically at room temperature) and to image precisely what is going on. This field remains one of the liveliest. A number of new experiments are reported here studying the dynamical evolution of domains and defects. Another phenomenon that played a key early role was the formation of vortices in the normal-to-superfluid transition in liquid helium-3. The complicated nature of the order parameter energy surface gives rise to a variety of intriguing effects. This too is still a vigorous field. Superconductivity is a special case because the symmetry that is broken is a gauge symmetry. This is also true in fundamental particle physics theories of relevance to cosmology, and for that reason experiments on superconductors are of particular interest to cosmologists. The situation in this case is more complicated because there are competing mechanisms of defect formation. Experiments in the field have not proved easy, either to perform or to interpret, but the papers in this collection show that good progress has been made of late. In recent years a new type of system has proved immensely fruitful, namely atomic Bose-Einstein or Fermi-gas condensates. Experiments on condensates with tunable parameters have in general provided broad support for the theory, and have also revealed a wide range of interesting and novel features, with intriguing possible analogues in cosmology (e.g. causal horizons and particle creation). The basic idea of the Kibble-Zurek mechanism has been shown to be relevant in this whole range of systems. But numerous complexities have also emerged, concerned for example with the role of inhomogeneity or the existence of composite defects. The field is still developing rapidly. Acknowledgments Finally, we would like to thank all the authors who have contributed to this issue, and the staff of Journal of Physics: Condensed Matter who have made it possible. Condensed matter analogues of cosmology contents Condensed matter analogues of cosmologyTom Kibble and Ajit Srivastava Symmetry breaking in nematic liquid crystals: analogy with cosmology and magnetismR Repnik, A Ranjkesh, V Simonka, M Ambrozic, Z Bradac and S Kralj Morphogenesis of defects and tactoids

Kibble, Tom; Srivastava, Ajit

2013-10-01

249

Synthesis and Biological Evaluation of Carbocyclic Analogues of Pachastrissamine  

PubMed Central

A series of carbocyclic analogues of naturally-occurring marine sphingolipid pachastrissamine were prepared and biologically evaluated. The analogues were efficiently synthesized via a tandem enyne/diene-ene metathesis reaction as a key step. We found that the analogue 4b exhibited comparable cytotoxicity and more potent inhibitory activity against sphingosine kinases, compared to pachastrissamine. Molecular modeling studies were conducted to provide more detailed insight into the binding mode of 4b in sphingosine kinase. In our docking model, pachastrissamine and 4b were able to effectively bind to the binding pocket of sphingosine kinase 1 as co-crystalized sphingosine. However, 4b showed a hydrophobic interaction with Phe192, which suggests that it contributes to its increased inhibitory activity against sphingosine kinase 1. PMID:25654428

Kwon, Yongseok; Song, Jayoung; Bae, Hoon; Kim, Woo-Jung; Lee, Joo-Youn; Han, Geun-Hee; Lee, Sang Kook; Kim, Sanghee

2015-01-01

250

Expansion of structure-activity studies of piperidine analogues of 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (GBR 12935) compounds by altering substitutions in the N-benzyl moiety and behavioral pharmacology of selected molecules.  

PubMed

A series of substituted N-benzyl analogues of the dopamine transporter (DAT) specific compound, 4-[2-(diphenylmethoxy)ethyl]-1-benzylpiperidine were synthesized and biologically characterized. Different 4'-alkyl, 4'-alkenyl, and 4'-alkynyl substituents were introduced in the phenyl ring of the benzyl moiety along with the replacement of the same phenyl ring by the isomeric alpha- and beta-naphthyl groups. Different polar substitutions at the 3'- and 4'-position were also introduced. Novel compounds were tested for their binding affinity at the dopamine, serotonin, and norepinephrine transporter systems in the brain by competing for [(3)H]WIN 35 428, [(3)H]citalopram, and [(3)H]nisoxetine, respectively. Selected compounds were also evaluated for their activity in inhibiting the uptake of [(3)H]dopamine. Binding results demonstrated that alkenyl and alkynyl substitutions at the 4'-position produced potent compounds in which compound 6 with a vinyl substitution was the most potent. In vivo evaluation of three selected compounds indicated that despite their high potency at the DAT, these compounds stimulated locomotor activity (LMA) less than cocaine when tested across similar dose ranges. In a drug discrimination study procedure, none of these three compounds generalized from cocaine in mice trained to discriminate 10 mg/kg cocaine from vehicle. In a 4 h time course LMA experiment, one of our previous lead piperidine derivatives (1a) showed considerable prolonged action. Thus, in this report, we describe a structure-activity relationship study of novel piperidine analogues assessed by both in vitro transporter assays and in vivo behavioral activity measurements. PMID:11806716

Dutta, Aloke K; Davis, Matthew C; Fei, Xiang-Shu; Beardsley, Patrick M; Cook, Charles D; Reith, Maarten E A

2002-01-31

251

Structural Analysis of the ?-2,3Sialyltransferase Cst-I from Campylobacter jejuni in Apo and Substrate-Analogue Bound Forms † , ‡  

Microsoft Academic Search

Sialic acid is an essential sugar in biology that plays key roles in numerous cellular processes and interactions. The biosynthesis of sialylated glycoconjugates is catalyzed by five distinct families of sialyltransferases. In the last 25 years, there has been much research on the enzymes themselves, their genes, and their reaction products, but we still do not know the precise molecular

Cecilia P. C. Chiu; Luke L. Lairson; Michel Gilbert; Warren W. Wakarchuk; Stephen G. Withers; Natalie C. J. Strynadka

2007-01-01

252

The influence of pre-existing basement structures on salt tectonics in the Upper Silurian Salina Group, Appalachian Basin, NE Pennsylvania: results from 3D seismic analysis and analogue modelling  

NASA Astrophysics Data System (ADS)

The Upper Silurian Salina Group in Pennsylvania's Appalachian basin consists of several hundred feet of highly deformable and mobile salt that was a significant influence on the tectonic and structural development of the Appalachian Mountains during the late Paleozoic. Understanding how halokinesis and décollement thrusting of the Salina Group has contributed to the present-day structure of the Appalachian Basin is of intense current interest due to the energy resource potential of the overlying Marcellus Shale and underlying Utica Shale. Seismic data suggest that halokinesis of the Salina Group in the Appalachian Basin might be strongly influenced by the presence of preexisting faults in the underlying Neoproterozoic basement, which suggests that these structures may have interacted with the Salina Group or its interior during deformation. We examine these apparent interactions in more detail using high-resolution 3D seismic data from the Appalachian Basin of NE Pennsylvania to identify and characterize salt tectonic-related structures developed above and within the Salina Group during orogenesis, verify their geographic association with major basement faults, and document how reactivation of these preexisting faults might have influenced later deformation within and above the salt units. We also present the results of sandbox modelling of thin-skinned thrusting in a salt-analogue décollement. Multiple runs in the presence and absence of preexisting basement structures provide insight into how the modern structures observed in the seismic data initiated and evolved during progressively more intense orogenesis, and better constrain the physical processes that control the structural linkage through the Salina décollement.

Harding, M. R.; Rowan, C. J.

2013-12-01

253

Influence of the Charge State on the Structures and Interactions of Vancomycin Antibiotics with Cell-Wall Analogue Peptides: Experimental and Theoretical Studies  

SciTech Connect

In this study we examined the effect of the charge state on the energetics and dynamics of dissociation of the non-covalent complex between the vancomycin and the cell wall peptide analogue N?,N?-diacetyl-L-Lys-D-Ala-D-Ala (V-Ac2KDADA). The binding energies between the vancomycin and the peptide were obtained from the RRKM modeling of the time- and energy resolved surface-induced dissociation (SID) experiments. Our results demonstrate that the stability of the complex toward fragmentation increases in the order: [V+Ac2KDADA+H]+2 < [V+Ac2KDADA+H]+ < [V+Ac2KDADA-H]-. Dissociation of the singly protonated and singly deprotonated complex is characterized by very large entropy effects indicating substantial increase in the conformational flexibility of the resulting products. The experimental threshold energies of 1.75 eV and 1.34 eV obtained for the [V+Ac2KDADA-H]- and [V+Ac2KDADA+H]+ , respectively, are in excellent agreement with the results of density functional theory (DFT) calculations. The increased stability of the deprotonated complex observed experimentally is attributed to the presence of three charged sites in the deprotonated complex as compared to only one charged site in the singly protonated complex. The low binding energy of 0.93 eV obtained for the doubly protonated complex suggests that this ion is destabilized by Coulomb repulsion between the singly protonated vancomycin and the singly protonated peptide comprising the complex.

Yang, Zhibo; Vorpagel, Erich R.; Laskin, Julia

2009-02-16

254

Bisdemethylcurcumin and structurally related hispolon analogues of curcumin exhibit enhanced prooxidant, anti-proliferative and anti-inflammatory activities in vitro.  

PubMed

Curcumin, a component of turmeric (Curcuma longa), exhibits anti-inflammatory and anti-proliferative activities through the generation of reactive oxygen species (ROS). Curcumin (diferuloylmethane) contains two hydroxyl, two methoxy and two phenyl groups but how these groups contribute to its activity is poorly understood. We synthesized analogues that varied in inclusion of these groups and compared their activity. We found that bisdemethylcurcumin (BDC) was more potent than curcumin as an anti-inflammatory agent as indicated by suppression of TNF-induced NF-kappaB activation, more potent as an anti-proliferative agent, and more potent in inducing ROS. Hispolon, which lacks one aromatic unit in relation to curcumin, also exhibited enhanced anti-inflammatory and anti-proliferative activities. When synthetic curcumin (Cur-S) was compared with bisdemethylcurcumin (BDC), hispolon, hispolon methyl ether (HME), dehydroxy hispolon (DH), hydroxy hispolon (HH), methoxy hispolon methyl ether (MHME), and methoxy hispolon (MH), we found that following order of anti-inflammatory activity: BDC=Hispolon>HME>HH>Cur-S>MHME>MH>DH; for anti-proliferative: Hispolon>BDC>MHME>Cur-S>MH>HME=HH>DH; and for prooxidant: BDC>Cur-S=MHME>HH>MH+HME>DH (254-1414 mean fluorescence intensity). Thus, dehydroxy hispolon was least potent for all three activities. Overall the results indicate that the substitution of a hydroxyl group for a methoxy group at the meta positions of the phenyl rings in curcumin significantly enhanced the anti-inflammatory activity, and the removal of phenyl ring at the 7(th) position of the heptadiene back bone and addition of hydroxyl group significantly increased the anti-proliferative activity of curcumin. PMID:20138025

Ravindran, Jayaraj; Subbaraju, Gottumukkala V; Ramani, Modukuri V; Sung, Bokyung; Aggarwal, Bharat B

2010-06-01

255

Bisdemethylcurcumin and Structurally Related Hispolon Analogues of Curcumin Exhibit Enhanced Prooxidant, Anti-Proliferative and Anti-inflammatory Activities in vitro  

PubMed Central

Curcumin, a component of turmeric (Curcuma longa), exhibits anti-inflammatory and anti-proliferative activities through the generation of reactive oxygen species (ROS). Curcumin (diferuloylemethane) contains two hydroxyl, two methoxy and two phenyl groups but how these groups contribute to its activity is poorly understood. We synthesized analogues that varied in inclusion of these groups and compared their activity. We found that bisdemethylcurcumin (BDC) was more potent than curcumin as an anti-inflammatory agent as indicated by suppression of TNF-induced NF-?B activation, more potent as an anti-proliferative agent, and more potent in inducing ROS. Hispolon, which lacks one aromatic unit in relation to curcumin, also exhibited enhanced anti-inflammatory and anti-proliferative activities. When synthetic curcumin (Cur-S) was compared with bisdemethylcurcumin (BDC), hispolon, hispolon methyl ether (HME), dehydroxy hispolon (DH), hydroxy hispolon (HH), methoxy hispolon methyl ether (MHME), and methoxy hispolon (MH), we found that following order of anti-inflammatory activity: BDC=Hispolon>HME> HH>Cur-S>MHME>MH>DH; for anti-proliferative Hispolon> BDC>MHME> Cur-S>MH>HME=HH>DH; and for prooxidant BDC>Cur-S=MHME>HH>MH+HME>DH (254-1414 mean fluorescence intensity). Thus dehydroxyhispolon was least potent for all three activities. Overall the results indicates that the substitution of a hydroxyl group for a methoxy group at the meta positions of the phenyl rings in curcumin significantly enhanced the anti-inflammatory activity, and the removal of phenyl ring at the 7th position of the heptadiene back bone and addition of hydroxyl group significantly increased the anti-proliferative activity of curcumin. PMID:20138025

Ravindran, Jayaraj; Subbaraju, Gottumukkala V.; Ramani, Modukuri V.; Sung, Bokyung; Aggarwal, Bharat B.

2010-01-01

256

Analogue modelling of syntectonic leucosomes in migmatitic schists  

NASA Astrophysics Data System (ADS)

Migmatites from the Cap de Creus tectonometamorphic belt display a wide variety of structures, from those formed when the leucosomes were melt-bearing, to those developed during solid-state deformation. The observed field structures have been modelled by means of analogue experiments. The materials used in the models are layered plasticine as a schist analogue, and chocolate as analogue of the crystallizing leucosome. A model for the development of syntectonic migmatites is proposed in which initial melt-bearing patches, preferentially formed within fertile pelitic layers, progressively evolve towards lens-shaped veins. Furthermore, heterogeneous deformation of anisotropic metasediments facilitates formation of extensional sites for further melt accumulation and transport. Melt crystallization implies a rapid increase in effective viscosity of leucosomes producing a reversal in competence contrast with respect to the enclosing schists. During the whole process, deformation localizes around crystallizing veins, giving rise to different and contrasting structures for melt-bearing and for solid-state stages.

Druguet, Elena; Carreras, Jordi

2006-10-01

257

STRUCTURES OF A KEY INTERACTION PROTEIN FROM THE TRYPANOSOMA BRUCEI EDITOSOME IN COMPLEX WITH SINGLE DOMAIN ANTIBODIES  

PubMed Central

Several major global diseases are caused by single-cell parasites called trypanosomatids. These organisms exhibit many unusual features including a unique and essential U-insertion-deletion RNA editing process in their single mitochondrion. Many key RNA editing steps occur in ~ 20S editosomes, which have a core of 12 proteins. Among these, the “interaction protein” KREPA6 performs a central role in maintaining the integrity of the editosome core and also binds to ssRNA. The use of llama single domain antibodies (VHH domains) accelerated crystal growth of KREPA6 from Trypanosoma brucei dramatically. All three structures obtained are heterotetramers with a KREPA6 dimer in the center, and one VHH domain bound to each KREPA6 subunit. Two of the resultant heterotetramers use complementarity determining region 2 (CDR2) and framework residues to form a parallel pair of beta strands with KREPA6 – a mode of interaction not seen before in VHH domain-antigen complexes. The third type of VHH domain binds in a totally different manner to KREPA6. Intriguingly, while KREPA6 forms tetramers in solution adding either one of the three VHH domains results in the formation of a heterotetramer in solution, in perfect agreement with the crystal structures. Biochemical solution studies indicate that the C-terminal tail of KREPA6 is involved in the dimerization of KREPA6 dimers to form tetramers. The implications of these crystallographic and solution studies for possible modes of interaction of KREPA6 with its many binding partners in the editosome are discussed. PMID:20969962

Wu, Meiting; Park, Young-jun; Pardon, Els; Turley, Stewart; Hayhurst, Andrew; Deng, Junpeng; Steyaert, Jan; Hol, Wim G. J.

2010-01-01

258

Transfer RNA structural change is a key element in the reassignment of the CUG codon in Candida albicans.  

PubMed

The human pathogenic yeast Candida albicans and a number of other Candida species translate the standard leucine CUG codon as serine. This is the latest addition to an increasing number of alterations to the standard genetic code which invalidate the theory that the code is frozen and universal. The unexpected finding that some organisms evolved alternative genetic codes raises two important questions: how have these alternative codes evolved and what evolutionary advantages could they create to allow for their selection? To address these questions in the context of serine CUG translation in C.albicans, we have searched for unique structural features in seryl-tRNA(CAG), which translates the leucine CUG codon as serine, and attempted to reconstruct the early stages of this genetic code switch in the closely related yeast species Saccharomyces cerevisiae. We show that a purine at position 33 (G33) in the C.albicans Ser-tRNA(CAG) anticodon loop, which replaces a conserved pyrimidine found in all other tRNAs, is a key structural element in the reassignment of the CUG codon from leucine to serine in that it decreases the decoding efficiency of the tRNA, thereby allowing cells to survive low level serine CUG translation. Expression of this tRNA in S.cerevisiae induces the stress response which allows cells to acquire thermotolerance. We argue that acquisition of thermotolerance may represent a positive selection for this genetic code change by allowing yeasts to adapt to sudden changes in environmental conditions and therefore colonize new ecological niches. PMID:8890179

Santos, M A; Perreau, V M; Tuite, M F

1996-09-16

259

Phonon analogue of topological nodal semimetals  

E-print Network

Recently, Kane and Lubensky proposed a mapping between bosonic phonon problems on isostatic lattices to chiral fermion systems based on factorization of the dynamical matrix [Nat. Phys. 10, 39 (2014)]. The existence of topologically protected zero modes in such mechanical problems is related to their presence in the fermionic system and is dictated by a local index theorem. Here we adopt the proposed mapping to construct a two-dimensional mechanical analogue of a fermionic topological nodal semimetal that hosts a robust bulk node in its linearized phonon spectrum. Such topologically protected soft modes with tunable wavevector may be useful in designing mechanical structures with fault-tolerant properties.

Hoi Chun Po; Yasaman Bahri; Ashvin Vishwanath

2014-10-06

260

Understanding complex structures in fold-and-thrust belts. Integration of geometric and growth strata analyses, paleomagnetism, AMS and analogue models in the Western termination of the Southern Pyrenees  

NASA Astrophysics Data System (ADS)

Classic 2D approaches have helped the understanding of the geometry and kinematics of fold-and-thrust belts belts (FAT belts) but are insufficient to unravel many natural cases. This is because deformation is 3D from the geometric point of view and, thus, cylindrical features may be considered as a simplification. On the other hand, deformation kinematics is usually complex, diachronic and poliphasic in real cases. Therefore, FAT belts have to be always considered in 4D. In this sense, the Southern Pyrenees is a perfect location to study the evolution of FAT belts because of the exceptional outcropping conditions of growth strata, the proven diachronic kinematics and the non-coaxial interference of deformation events. Within the vast catalogue of complex structures that includes superposed folding, conical and plunging folds, oblique thrust ramps, etc here, we have selected the westernmost termination of the South Pyrenean sole thrust to illustrate how the integration of geometric and kinematic analysis can help unraveling complex structures in FAT belts. The San Marzal pericline (4 km2 surface extension) is the lateral termination of the Sto. Domingo deca-kilometric fold. San Marzal looks like a large 70° plunging cylindrical structure. However the large magnitude (? 60-70°) of vertical axis rotations accommodated between its flanks cannot be explained without a conical geometry. In this work we will show how the structural analysis performed on this structure has disentangled its complex geometry. This analyses comprises several hundreds of bedding data, joints and veins and more than 150 standard paleomagnetic and AMS sites. Besides, we will show how the kinematic information derived from magnetostratigraphic sections (more than 8 km of sampled profiles) has helped to constraint the folding and rotation ages and velocities. Finally, all these complex geometric and kinematic features have inspired us to build an analogue model where we can explore the 3D distribution of strain ellipsoids.

Pueyo, Emilio L.; Sánchez, Elisa; Oliva-Urcia, Belén; José Ramón, Ma

2014-05-01

261

Conformationally constrained analogues of 2-arachidonoylglycerol.  

PubMed

Novel monocyclic analogues of 2-arachidonoylglycerol (2-AG) were designed in order to explore the pharmacophoric conformations of this endocannabinoid ligand at the key cannabinergic proteins. All 2-arachidonoyl esters of 1,2,3-cyclohexanetriol [meso-7 (AM5504), (+/-)-8 (AM5503), and meso-9 (AM5505)] were synthesized by regioselective acylation of 2,3-dihydroxycyclohexanone followed by selective reductions. The optically active isomers (+)-8 (AM4434) and (-)-8 (AM4435) were synthesized from (2S,3S)- and (2R,3R)-2,3-dihydroxycyclohexanone, respectively, via a chemoenzymatic route. These head group constrained and conformationally restricted analogues of 2-AG as well as the 1-keto precursors were evaluated as substrates for the endocannabinoid deactivating hydrolytic enzymes monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH), and also were tested for their affinities for CB1 and CB2 cannabinoid receptors. The observed biochemical differences between these ligands can help define the conformational requirements for 2-AG activity at each of the above endocannabinoid protein targets. PMID:17826996

Vadivel, Subramanian K; Vardarajan, Sundararaman; Duclos, Richard I; Wood, JodiAnne T; Guo, Jianxin; Makriyannis, Alexandros

2007-11-01

262

The 'Vertical Structure and Diabatic Processes of the Madden-Julian Oscillation' model evaluation project: Overview and key results (Invited)  

NASA Astrophysics Data System (ADS)

The Madden-Julian oscillation (MJO) is the dominant mode of tropical sub-seasonal (30-60 day) variability. By modulating regional monsoon circulation and precipitation, interacting with ENSO and influences modes of extra-tropical variability (e.g., the NAO), the MJO provides a key source of weekly and monthly predictability globally. Despite this, most weather and climate models exhibit large biases in their simulations of the MJO. We will introduce a model evaluation project, endorsed by YoTC and GASS, designed to identify and reduce sources of error in the models' MJO representations. A key advantage of this project over previous intercomparisons is that temperature, moisture and momentum tendencies have been requested from all sub-grid parameterization schemes. This allows detailed analysis of the links between biases in MJO activity and biases in the vertical profiles of diabatic heating, moistening and momentum. The project comprises three components: 20-year simulations, from which the overall level of MJO activity can be assessed; serial 2-day hindcasts of two strong events in winter 2009-2010, in which the behavior of model parameterizations can be evaluated close to the initial, observed state; and serial 20-day hindcasts of the same two MJO events, which bridge the gap between the other two components by permitting analysis of the degradation of the simulated MJO from the initial state towards the model's climatology. Analysis of the 20-year simulations suggests that many proposed process-oriented MJO metrics, such as the relationship between precipitation and the vertical structure of relative humidity, do not sufficiently distinguish between those models that simulate the MJO well and those that simulate it poorly. It is assumed that the processes described by these metrics are necessary, but not sufficient, for an adequate simulation of the MJO in GCMs. Analysis of the 2-day hindcasts demonstrates that models develop substantial biases in upper-level temperature and humidity, evaluated against YoTC analyses, within 48 hours. These biases stem from large differences in cloud cover above the freezing level in models, which lead to discrepancies in the magnitude and even sign of the radiative temperature increments; this points to errors in cloud-radiative interactions in these models. In the 20-day hindcasts, there is no relationship between a model's ability to predict the MJO and its vertical profile of diabatic heating; models with similar diabatic-heating profiles have very different levels of skill in these hindcasts. A more consistent association is found between MJO skill and diabatic-moistening profiles, with high-skill models showing a clear transition from shallow moistening in suppressed conditions to deep moistening during the active phase. We will present an overview of the evaluation project, its goals and objectives; highlight key results from each components of the project; and discuss the next steps for further analysis, including the dissemination of data to the wider community.

Klingaman, N. P.; Jiang, X.; Xavier, P.; Petch, J.; Waliser, D. E.; Woolnough, S.

2013-12-01

263

Alternative administration of camptothecin analogues.  

PubMed

In order to improve the therapeutic index of camptothecin (CPT) analogues, alternative administration of CPT analogues is being evaluated. Topotecan, irinotecan, rubitecan, lurtotecan and 9-aminocamptothecin have been administered orally with response rates equivalent to that seen after intravenous administration, where applicable. Oral availability and administration of some of the newer CPT analogues, including diflomotecan (BN80915) and grimatecan (ST1481), have also shown promising results. Aerosolisation of liposomal 9-nitrocamptothecin has been studied in patients with advanced malignancies involving the lung, demonstrating systemic antitumour activity. Intrathecal administration of topotecan has been studied in children with refractory neoplastic meningitis. It is well tolerated and associated with some antitumour activity. Intraperitoneal administration of topotecan as consolidation therapy in patients with ovarian cancer has shown promising results. Transdermal administration of rubitecan has been studied in mice. So far, no CPT has been approved for an alternative route of administration. PMID:16296757

Glaberman, Ursa; Rabinowitz, Ian; Verschraegen, Claire F

2005-03-01

264

Dimetallaborane analogues of pentaborane.  

PubMed

The structures of five-vertex dimetallaboranes Cp2M2B3H7 (Cp = ?(5)-C5H5) of the second and third row transition metals, including the experimentally known Cp*2Rh2B3H7 (Cp* = ?(5)-Me5C5), have been investigated by density functional theory. The predicted low-energy structures for Cp2M2B3H7 (M = Rh, Ir) are tetragonal pyramids similar to Cp*2Rh2B3H7 and pentaborane-9 B5H9 and consistent with their 14 Wadean skeletal electrons. Two Cp*2Rh2B3H7 structures with the same central Rh2B3 tetragonal prism are found with energies within ?1 kcal mol(-1) of each other, consistent with the experimental observation of two isomers in solution. The electron-richer Cp2M2B3H7 (M = Pd, Pt) systems having 16 Wadean skeletal electrons are predicted to exhibit more open structures analogous to the known structure for the valence isoelectronic pentaborane-11 B5H11. Trigonal bipyramids with the metal atoms at equatorial vertices are typically found to be low-energy structures for the hypoelectronic Cp2M2B3H7 systems (M = Ru, Os, Re, Mo, W, Ta). In addition, the low-energy Cp2Re2B3H7 structures of the rhenium derivatives Cp2Re2B3H7 provide examples of structures based on a central Re2B2 tetrahedron with the Re-Re edge bridged by the third boron atom. Such structures can be derived from a trigonal bipyramid by the rupture of one of the axial-equatorial edges. PMID:25797320

Brânzanic, Adrian M V; Lupan, Alexandru; King, R Bruce

2015-04-01

265

1,19-seco-Avermectin Analogues from a ?aveCDE Mutant Streptomyces avermectinius Strain.  

PubMed

Three new 1,19-seco-avermectin (AVE) analogues were isolated from the ?aveCDE mutant Streptomyces avermectinius strain. Their structures were elucidated by detailed spectroscopic analysis. This is the first report of 1,19-seco-AVE analogues. In an in vitro assay these compounds displayed cytotoxicity against Saos-2, MG-63, and B16 cell lines. PMID:25611131

Sun, Peng; Zhao, Qunfei; Wu, Zhuhua; Zhang, Wen; Liu, Wen

2015-02-27

266

Development of Stable Phosphohistidine Analogues  

PubMed Central

Protein phosphorylation is one of the most common and extensively studied posttranslational modifications (PTMs). Compared to the O-phosphorylation of Ser, Thr, and Tyr residues, our understanding of histidine phosphorylation is relatively limited, particularly in higher eukaryotes, due to technical difficulties stemming from the intrinsic instability and isomerism of phosphohistidine (pHis). We report the design and synthesis of stable and nonisomerizable pHis analogues. These pHis analogues were successfully utilized in solid-phase peptide synthesis and semi-synthesis of histone H4. Significantly, the first antibody that specifically recognizes pHis was obtained using the synthetic peptide as the immunogen. PMID:20879710

Kee, Jung-Min; Villani, Bryeanna; Carpenter, Laura R.

2011-01-01

267

Genuine modern analogues of Precambrian stromatolites from caldera lakes of Niuafo'ou Island, Tonga.  

PubMed

Calcareous or dolomitic, often secondarily silicified, laminated microbial structures known as stromatolites are important keys to reconstruct the chemical and biotic evolution of the early ocean. Most authors assume that cyanobacteria-associated microbialitic structures described from Shark Bay, Western Australia, and Exuma Sound, Bahamas, represent modern marine analogues for Precambrian stromatolites. Although they resemble the Precambrian forms macroscopically, their microstructure and mineralogical composition differ from those characterizing their purported ancient counterparts. Most Precambrian stromatolites are composed of presumably in situ precipitated carbonates, while their assumed modern marine analogues are predominantly products of accretion of grains trapped and bound by microbial, predominantly cyanobacterial, benthic mats and biofilms and only occasionally by their physicochemical activity. It has therefore been suggested that the carbonate chemistry of early Precambrian seawater differed significantly from modern seawater, and that some present-day quasi-marine or non-marine environments supporting growth of calcareous microbialites reflect the hydrochemical conditions controlling the calcification potential of Precambrian microbes better than modern seawater. Here we report the discovery of a non-marine environment sustaining growth of calcareous cyanobacterial microbialites showing macroscopic and microscopic features resembling closely those described from many Precambrian stromatolites. PMID:16365738

Kazmierczak, Józef; Kempe, Stephan

2006-03-01

268

Synthesis of novel benzoxaborole-containing phenylalanine analogues  

Microsoft Academic Search

The synthesis of novel benzoxaborole-containing phenylalanine analogues 2 and 3 has been developed. The key steps involve the preparation of appropriate precursors from the readily available amino acids and the formation of benzoxaborole ring directly in the corresponding amino acid fragment. The resulting compounds 2–3 show improved water solubility at physiological pH, suggesting their potential use as boron delivery agents

Xianfeng Li; Jacob J. Plattner; Vincent Hernandez; Charles Z. Ding; Wei Wu; Yang Yang; Musheng Xu

2011-01-01

269

Arctic Mars Analogue Svalbard Expedition 2007  

NASA Astrophysics Data System (ADS)

This abstract summarizes the rover, space flight hardware testing and human rover interactions that took place on the Arctic Mars Analogue Svalbard Expedition 2006 and will present the results of life detection analysis undertaken in this Mars analogue en

Steele, A.; Amundsen, H. E. F.

2007-03-01

270

Models and Analogues  

ERIC Educational Resources Information Center

How do teachers help children understand the difference between the structure of a flower and that of a root? Depending on the time of year this activity is quite easy. Get a bunch of flowers, germinate some chickpeas and raid the kitchen for carrots and beetroots--the children can experience the "real thing". But what if teachers want the…

Maloney, Jane; Curtis, Sheila

2012-01-01

271

U-Pb Composition and Shock Microstructures of In-Situ Accessory Phases Across the Vredefort Impact Structure, South Africa: A Terrestrial Analogue for Dating the Lunar Surface and Other Planetary Bodies  

NASA Astrophysics Data System (ADS)

Accessory phases (i.e. zircon, monazite) co-exist within individual samples of the Vredefort dome, with a dichotomy of U-Pb ages and microstructural evolution. Vredefort is a terrestrial analogue for complex craters on other planetary bodies.

Davis, C. L.; Moser, D. E.

2015-02-01

272

Cytotoxicity of 6,16-disubstituted analogues of (-)-vincadifformine.  

PubMed

Eight analogues of (-)-16-chloro-1-dehydro-6S-bromovincadifformine 1 were synthesized and evaluated for cytotoxicity in L1210 cell culture. None of the new compounds was more active than 1 but the modulation at C6, C16 and on the aromatic ring at C10 informs about structure-activity relationships within this series. PMID:11814799

Lewin, Guy; Hocquemiller, Reynald; Schaeffer, Corinne; Lambert, Pierre-Hervé; Léonce, Stéphane; Pierré, Alain

2002-02-11

273

Synthesis and Cytotoxicity of Semisynthetic Withalongolide A Analogues  

PubMed Central

The natural product withaferin A exhibits potent antitumor activity and other diverse pharmacological activities. The recently discovered withalongolide A, a C-19 hydroxylated congener of withaferin A, was recently reported to possess cytotoxic activity against head and neck squamous cell carcinomas. Semisynthetic acetylated analogues of withalongolide A were shown to be considerably more cytotoxic than the parent compound. To further explore the structure–activity relationships, 20 new semisynthetic analogues of withalongolide A were synthesized and evaluated for cytotoxic activity against four different cancer cell lines. A number of derivatives were found to be more potent than the parent compound and withaferin A. PMID:24273633

2013-01-01

274

Naturally occurring crystalline phases: analogues for radioactive waste forms  

SciTech Connect

Naturally occurring mineral analogues to crystalline phases that are constituents of crystalline radioactive waste forms provide a basis for comparison by which the long-term stability of these phases may be estimated. The crystal structures and the crystal chemistry of the following natural analogues are presented: baddeleyite, hematite, nepheline; pollucite, scheelite;sodalite, spinel, apatite, monazite, uraninite, hollandite-priderite, perovskite, and zirconolite. For each phase in geochemistry, occurrence, alteration and radiation effects are described. A selected bibliography for each phase is included.

Haaker, R.F.; Ewing, R.C.

1981-01-01

275

Synthesis and bioactivity of analogues of the marine antibiotic tropodithietic acid  

PubMed Central

Summary Tropodithietic acid (TDA) is a structurally unique sulfur-containing antibiotic from the Roseobacter clade bacterium Phaeobacter inhibens DSM 17395 and a few other related species. We have synthesised several structural analogues of TDA and used them in bioactivity tests against Staphylococcus aureus and Vibrio anguillarum for a structure–activity relationship (SAR) study, revealing that the sulfur-free analogue of TDA, tropone-2-carboxylic acid, has an antibiotic activity that is even stronger than the bioactivity of the natural product. The synthesis of this compound and of several analogues is presented and the bioactivity of the synthetic compounds is discussed. PMID:25161739

Rabe, Patrick; Klapschinski, Tim A; Brock, Nelson L; Citron, Christian A; D’Alvise, Paul; Gram, Lone

2014-01-01

276

Synthesis and bioactivity of analogues of the marine antibiotic tropodithietic acid.  

PubMed

Tropodithietic acid (TDA) is a structurally unique sulfur-containing antibiotic from the Roseobacter clade bacterium Phaeobacter inhibens DSM 17395 and a few other related species. We have synthesised several structural analogues of TDA and used them in bioactivity tests against Staphylococcus aureus and Vibrio anguillarum for a structure-activity relationship (SAR) study, revealing that the sulfur-free analogue of TDA, tropone-2-carboxylic acid, has an antibiotic activity that is even stronger than the bioactivity of the natural product. The synthesis of this compound and of several analogues is presented and the bioactivity of the synthetic compounds is discussed. PMID:25161739

Rabe, Patrick; Klapschinski, Tim A; Brock, Nelson L; Citron, Christian A; D'Alvise, Paul; Gram, Lone; Dickschat, Jeroen S

2014-01-01

277

Optical Properties of Titan's Aerosol Analogues  

NASA Astrophysics Data System (ADS)

In the upper Titan's atmosphere its main constituents, CH4 and N2, are photolyzed and radiolyzed by solar photons and magnetospheric electrons. The primary products of these chemical interactions evolve to heavier organic compounds which are likely to associate to form the haze layers observed on Titan's upper atmosphere. Different theories and models have been used to explain the physical, chemical and optical properties of the haze material, but only with limited success. Among the parameters involved in these models, the complex refractive index is one of the most critical due to the influence that chemical composition and structural organization of the solid have on the n and k values. As part of a continued systematical study for the synthesis and characterization of Titan's aerosol analogues initiated in our group, we have subjected mixtures of CH4 in N2 to laser irradiation to produce layer of aerosol analogues. A set of optical properties values directly calculated from the transmission and reflectance curves, as well as a chemical characterization, by tandem mass spectroscopy, of the laboratory analogues will be presented. Our experimental protocol avoids some of the difficulties usually faced on laboratory simulations (over-irradiation, contamination with atmospheric oxygen, accurate ratio of initial gas mixture), porosity influences will also be discussed. The optical values can be used to determine how the chemical and optical properties of these aerosols influence the matching with the observed geometric albedo spectrum and how they participate in the radiative equilibrium processes in Titan's atmosphere. They will certainly help in the interpretation of the observations made by the Huygens descend through Titan's atmosphere last January and in all the new information about Titan generated since then. Financial support from CONACyT (40449) and PROMEP (103.5/03/1134) is acknowledged. SIRJ acknowledges a travel grant from PIFI 3.2.

Ramirez, Sandra I.; Contreras, G.; Agarwal, V.

2006-09-01

278

Review of Insulin and its Analogues in Diabetes Mellitus  

PubMed Central

Diabetes is a metabolic disorder where in human body does not produce or properly uses insulin, a hormone that is required to convert sugar, starches and other food into energy. Diabetes finally leads to more complications and to prevent these complications insulin and its analogues are used. After more than half a century of treating diabetics with animal insulin’s, recombinant DNA technologies and advanced protein chemistry made human insulin preparations available in the early 1980s. As the next step, over the last decade, insulin analogues were constructed by changing the structure of the native protein with the goal of improving the therapeutic properties of it, because the pharmacokinetic characteristics of rapid, intermediate and long-acting preparations of human insulin make it almost impossible to achieve sustained normoglycemia. The first clinically available insulin analogue, lispro, confirmed the hopes by showing that improved glycaemic control can be achieved without an increase in hypoglycaemic events. Two new insulin analogues, insulin glargine and insulin aspart, have recently been approved for clinical use in the United States and several other analogues are being intensively tested. PMID:24826038

Mane, Krishnappa; Chaluvaraju, KC; Niranjan, MS; Zaranappa, TR; Manjuthej, TR

2012-01-01

279

New rubrolide analogues as inhibitors of photosynthesis light reactions.  

PubMed

Natural products called rubrolides have been investigated as a model for the development of new herbicides that act on the photosynthesis apparatus. This study comprises a comprehensive analysis of the photosynthesis inhibitory ability of 27 new structurally diverse rubrolide analogues. In general, the results revealed that the compounds exhibited efficient inhibition of the photosynthetic process, but in some cases low water solubility may be a limiting factor. To elucidate their mode of action, the effects of the compounds on PSII and PSI, as well as their partial reaction on chloroplasts and the chlorophyll a fluorescence transients were measured. Our results showed that some of the most active rubrolide analogues act as a Hill reaction inhibitors at the QB level by interacting with the D1 protein at the reducing side of PSII. All of the active analogues follow Tice's rule of 5, which indicates that these compounds present physicochemical properties suitable for herbicides. PMID:25748644

Varejão, Jodieh O S; Barbosa, Luiz C A; Ramos, Gabriela Álvarez; Varejão, Eduardo V V; King-Díaz, Beatriz; Lotina-Hennsen, Blas

2015-04-01

280

Design of novel CSA analogues as potential safeners and fungicides.  

PubMed

Study of safeners has been seldom reported in literature. In this work, a series of novel acylsulfamoylbenzamide analogues was designed and synthesized with newly developed safener cyprosulfamide (CSA) as the leading compound. The activity assay against the herbicide thiencarbazone-methyl (TCM) on maize revealed that fifteen compounds showed better protective effect than CSA on the fresh weight of aerial parts, twelve compounds exhibited better activity on the dry weight of aerial parts. Remarkably, two compounds (6Ih, 7II) had protective effect on the four aspects of TCM treated maize. Further antifungal assay showed their excellent activity against Physollospora piricola. The structure-activity relationships of CSA analogues as safeners and fungicides were discussed and it might be valuable for further molecular modification of new CSA analogues. PMID:25582601

Zheng, Yang; Liu, Bin; Gou, Zhaopin; Li, Yao; Zhang, Xiao; Wang, Yanqing; Yu, Shujing; Li, Yonghong; Sun, Dequn

2015-02-15

281

Synthesis and antifungal activity of novel streptochlorin analogues.  

PubMed

Streptochlorin, first isolated as a new antibiotic in 1988 from the lipophilic extracts of the mycelium of a Streptomyces sp, is an indole natural products with a variety of biological activities. Based on the methods developed for the synthesis of pimprinine in our laboratory, we have synthesized a series of indole-modified streptochlorin analogues and measured their activities against seven phytopathogenic fungi. Some of the analogues displayed good activity in the primary assays, and the seven compounds 10b, 10c, 11e, 13e, 21, 22c and 22e (shown in Figure 1) were identified as the most promising candidates for further study. Structural optimization is still ongoing with the aim of discovering synthetic analogues with improved antifungal activity. PMID:25633493

Zhang, Ming-Zhi; Chen, Qiong; Xie, Cai-Hong; Mulholland, Nick; Turner, Sarah; Irwin, Dianne; Gu, Yu-Cheng; Yang, Guang-Fu; Clough, John

2015-03-01

282

Migrastatin analogues target fascin to block tumour metastasis  

SciTech Connect

Tumour metastasis is the primary cause of death of cancer patients. Development of new therapeutics preventing tumour metastasis is urgently needed. Migrastatin is a natural product secreted by Streptomyces, and synthesized migrastatin analogues such as macroketone are potent inhibitors of metastatic tumour cell migration, invasion and metastasis. Here we show that these migrastatin analogues target the actin-bundling protein fascin to inhibit its activity. X-ray crystal structural studies reveal that migrastatin analogues bind to one of the actin-binding sites on fascin. Our data demonstrate that actin cytoskeletal proteins such as fascin can be explored as new molecular targets for cancer treatment, in a similar manner to the microtubule protein tubulin.

Chen, L.; Jakoncic, J.; Yang, S.; Zhang, J.; Huang, X.Y.

2010-04-15

283

Creation of Readily Accessible and Orally Active Analogue of Cortistatin A  

PubMed Central

Syntheses of structurally simplified analogues of cortistatin A (1), a novel antiangiogenic steroidal alkaloid from Indonesian marine sponge, and their biological activities were investigated. The analogues were designed by considering the 3-D structure of 1. Compound 30, in which the isoquinoline moiety was appended to the planar tetracyclic core structure, showed potent antiproliferative activity against human umbilical vein endothelial cells (HUVECs) together with high selectivity and also showed in vivo antiangiogenic activity and significant antitumor effect by oral administration. PMID:24900528

2012-01-01

284

A convergent approach to cryptophycin 52 analogues: synthesis and biological evaluation of a novel series of fragment a epoxides and chlorohydrins.  

PubMed

Cryptophycin 52 is a synthetic derivative of Cryptophycin 1, a potent antimicrotubule agent isolated from cyanobacteria. In an effort to increase the potency and water solubility of the molecule, a structure-activity relationship study (SAR) was initiated around the phenyl ring of fragment A. These Cryptophycin 52 analogues were accessed using a Wittig olefination reaction between various triphenylphosphonium salts and a key intermediate aldehyde prepared from Cryptophycin 53. Substitution on the phenyl ring of fragment A was well tolerated, and several of these analogues were equally or more potent than Cryptophycin 52 when evaluated in vitro in the CCRF-CEM leukemia cell line and in vivo against a murine pancreatic adenocarcinoma. PMID:12825938

Al-Awar, Rima S; Ray, James E; Schultz, Richard M; Andis, Sherri L; Kennedy, Joseph H; Moore, Richard E; Liang, Jian; Golakoti, Trimurtulu; Subbaraju, Gottumukkala V; Corbett, Thomas H

2003-07-01

285

Studies of the Structure and Composition of Rhenium-1,1-Hydroxyethylidenediphosphonate (HEDP) Analogues of the Radiotherapeutic Agent (186)ReHEDP.  

PubMed

Complexes of technetium with diphosphonate ligands are widely used for the imaging and diagnosis of bone disease and most especially metastatic bone cancer. Analogous complexes of radioactive rhenium ((186)Re) with the ligand H(4)HEDP, 1,1-hydroxyethylidenediphosphonate, have been shown to be effective palliatives for the treatment of the intense pain associated with metastatic bone cancer. We have synthesized several of these analogs using nonradioactive Re and have structurally characterized them using EXAFS (extended X-ray absorption fine structure) spectroscopy. One complex synthesized via the substitution reaction of HEDP with trans-[(py)(4)(O)(2)Re]Cl in absolute ethanol appears to be the 1:1 salt of the tris-HEDP complex anion with the starting Re cation, [(py)(4)(O)(2)Re][Re(H(2)HEDP)(3)]. Three other materials, all synthesized via reduction of perrhenate by stannous chloride in the presence of excess H(4)HEDP ligand, are quite different in structure from the material formed by substitution. The principal difference is that each of these contains Re-Re bonds and is formulated as oligomers. The material with a large excess of reductant has Re-Re bonds of ca. 2.4 Å and is best modeled as a linear tetramer of rhenium atoms bridged by HEDP ligands which also bind an equivalent number of tin atoms with additional HEDP ligands. It is formulated as Li(x)()[Re(4)(OH)(2)Sn(4)(HEDP)(12)]. The material formed with the least amount of reducing agent is best modeled as a triangular cluster of rhenium atoms bicapped by two HEDP ligands and bridged to three tin atoms by HEDP to form a complex Li(x)()[Re(3)Sn(3)(HEDP)(8)]. It also has Re-Re bonds but of a significantly longer distance, ca. 2.8 Å. A material with an intermediate amount of reducing agent, prepared in a manner most closely resembling the medically effective palliative agent, appears to contain a mixture of these, and perhaps other, oligomers. PMID:11669957

Elder, R. C.; Yuan, Jie; Helmer, Bella; Pipes, David; Deutsch, Karen; Deutsch, Edward

1997-07-01

286

Crystal Structures of Human MdmX (HdmX) in Complex with p53 Peptide Analogues Reveal Surprising Conformational Changes*  

PubMed Central

p53 tumor suppressor activity is negatively regulated through binding to the oncogenic proteins Hdm2 and HdmX. The p53 residues Leu26, Trp23, and Phe19 are crucial to mediate these interactions. Inhibiting p53 binding to both Hdm2 and HdmX should be a promising clinical approach to reactivate p53 in the cancer setting, but previous studies have suggested that the discovery of dual Hdm2/HdmX inhibitors will be difficult. We have determined the crystal structures at 1.3 Å of the N-terminal domain of HdmX bound to two p53 peptidomimetics without and with a 6-chlorine substituent on the indole (which binds in the same subpocket as Trp23 of p53). The latter compound is the most potent peptide-based antagonist of the p53-Hdm2 interaction yet to be described. The x-ray structures revealed surprising conformational changes of the binding cleft of HdmX, including an “open conformation” of Tyr99 and unexpected “cross-talk” between the Trp and Leu pockets. Notably, the 6-chloro p53 peptidomimetic bound with high affinity to both HdmX and Hdm2 (Kd values of 36 and 7 nm, respectively). Our results suggest that the development of potent dual inhibitors for HdmX and Hdm2 should be feasible. They also reveal possible conformational states of HdmX, which should lead to a better prediction of its interactions with potential biological partners. PMID:19153082

Kallen, Joerg; Goepfert, Arnaud; Blechschmidt, Anke; Izaac, Aude; Geiser, Martin; Tavares, Gisele; Ramage, Paul; Furet, Pascal; Masuya, Keiichi; Lisztwan, Joanna

2009-01-01

287

Discovery of Desketoraloxifene Analogues as Inhibitors of Mammalian, Pseudomonas aeruginosa, and NAPE Phospholipase D Enzymes  

PubMed Central

Phospholipase D (PLD) hydrolyses cellular lipids to produce the important lipid second messenger phosphatidic acid. A PLD enzyme expressed by Pseudomonas aeruginosa (PldA) has been shown to be important in bacterial infection, and NAPE-PLD has emerged as being key in the synthesis of endocannabinoids. In order to better understand the biology and therapeutic potential of these less explored PLD enzymes, small molecule tools are required. Selective estrogen receptor modulators (SERMs) have been previously shown to inhibit mammalian PLD (PLD1 and PLD2). By targeted screening of a library of SERM analogues, additional parallel synthesis, and evaluation in multiple PLD assays, we discovered a novel desketoraloxifene-based scaffold that inhibited not only the two mammalian PLDs but also structurally divergent PldA and NAPE-PLD. This finding represents an important first step toward the development of small molecules possessing universal inhibition of divergent PLD enzymes to advance the field. PMID:25384256

Scott, Sarah A.; Spencer, Cierra T.; O’Reilly, Matthew C.; Brown, Kyle A.; Lavieri, Robert R.; Cho, Chul-Hee; Jung, Dai-Il; Larock, Richard C.; Brown, H. Alex; Lindsley, Craig W.

2015-01-01

288

Metamorphic core complexes vs. synkinematic plutons in continental extension setting: insights from key structures (Shandong Province, eastern China)  

E-print Network

) the exhumation of the Late Jurassic-Early Cretaceous Linglong MCC below the SE-dipping Linglong detachment fault by partially-melted lower to middle crust upward into the Linglong MCC should be revised to Late Jurassic-Early Cretaceous period. Key-words: Mesozoic extension, eastern Asia, Metamorphic Core Complex, synkinematic pluton

Paris-Sud XI, Université de

289

Ultradeep Pyrosequencing and Molecular Modeling Identify Key Structural Features of Hepatitis B Virus RNase H, a Putative Target for Antiviral Intervention  

PubMed Central

Last-generation nucleoside/nucleotide analogues are potent against hepatitis B virus (HBV) and have a high barrier to resistance. However, delayed responses have been observed in patients previously exposed to other drugs of the same class, long-term resistance is possible, and cure of infection cannot be achieved with these therapies, emphasizing the need for alternative therapeutic approaches. The HBV RNase H represents an interesting target because its enzyme activity is essential to the HBV life cycle. The goal of our study was to characterize the structure of the HBV RNase H by computing a 3-dimensional molecular model derived from E. coli RNase H and analyzing 2,326 sequences of all HBV genotypes available in public databases and 958,000 sequences generated by means of ultradeep pyrosequencing of sequences from a homogenous population of 73 treatment-naive patients infected with HBV genotype D. Our data revealed that (i) the putative 4th catalytic residue displays unexpected variability that could be explained by the overlap of the HBx gene and has no apparent impact on HBV replicative capacity and that (ii) the C-helix-containing basic protrusion, which is required to guide the RNA/DNA heteroduplex into the catalytic site, is highly conserved and bears unique structural properties that can be used to target HBV-specific RNase H inhibitors without cross-species activity. The model shows substantial differences from other known RNases H and paves the way for functional and structural studies as a prerequisite to the development of new inhibitors of the HBV cell cycle specifically targeting RNase H activity. PMID:24173223

Hayer, Juliette; Rodriguez, Christophe; Germanidis, Georgios; Deléage, Gilbert; Zoulim, Fabien; Pawlotsky, Jean-Michel

2014-01-01

290

Comparative analysis of the electrostatic potentials of some structural analogues of 2,3,7,8-tetrachlorodibenzo-p-dioxin and of related aromatic systems  

SciTech Connect

An ab initio STO-5G computational analysis of the electrostatic potentials of four structural analogs of the highly toxic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and four related aromatic systems (benzo(a)pyrene, benz(a)anthracene and two isomeric benzoflavones) was carried out. The systems, to varying degrees, induce aryl hydrocarbon hydroxylase activity and are believed to interact with the same cytosolic receptor in initiating their biochemical responses. It was found that a high degree of activity appears to require negative potentials that are non-overlapping above all or most of the lateral regions, with an observed optimum range of magnitudes. In systems with central oxygens, it is required that the negative oxygen potentials be small and weak; however, oxygen negative regions in the molecule are not necessary for high activity. The observed differences between the potential patterns of the four aromatic systems and those of TCDD and its active analogs may reflect an inherent dissimilarity in the nature of their interactions with the cytosolic receptor.

Murray, J.S.; Evans, P.; Politzer, P.

1990-01-01

291

Discovery and structure-activity relationships study of novel thieno[2,3-b]pyridine analogues as hepatitis C virus inhibitors.  

PubMed

Current treatment for hepatitis C is barely satisfactory, there is an urgent need to develop novel agents for combating hepatitis C virus infection. This study discovered a new class of thieno[2,3-b]pyridine derivatives as HCV inhibitors. First, a hit compound characterized by a thienopyridine core was identified in a cell-based screening of our privileged small molecule library. And then, structure activity relationship study of the hit compound led to the discovery of several potent compounds without obvious cytotoxicity in vitro (12c, EC50=3.3?M, SI >30.3, 12b, EC50=3.5?M, SI >28.6, 10l, EC50=3.9?M, SI >25.6, 12o, EC50=4.5?M, SI >22.2, respectively). Although the mechanism of them had not been clearly elucidated, our preliminary optimization of this class of compounds had provided us a start point to develop new anti-HCV agents. PMID:24529869

Wang, Ning-Yu; Zuo, Wei-Qiong; Xu, Ying; Gao, Chao; Zeng, Xiu-Xiu; Zhang, Li-Dan; You, Xin-Yu; Peng, Cui-Ting; Shen, Yang; Yang, Sheng-Yong; Wei, Yu-Quan; Yu, Luo-Ting

2014-03-15

292

Hexanuclear, heterometallic, Ni?Ln? complexes possessing O-capped homo- and heterometallic structural subunits: SMM behavior of the dysprosium analogue.  

PubMed

The reaction of hetero donor chelating mannich base ligand 6,6'-{(2-(dimethylamino)ethylazanediyl)bis(methylene)}bis(2-methoxy-4-methylphenol) with Ni(ClO4)2·6H2O and lanthanide(III) salts [Dy(III) (1); Tb(III) (2); Gd (III) (3); Ho(III) (4); and Er(III) (5)] in the presence of triethylamine and pivalic acid afforded a series of heterometallic hexanuclear Ni(II)-Ln(III) coordination compounds, [Ni3Ln3(?3-O)(?3-OH)3(L)3(?-OOCCMe3)3]·(ClO4)·wCH3CN·xCH2Cl2·yCH3OH·zH2O [for 1, w = 8, x = 3, y = 0, z = 5.5; for 2, w = 0, x = 5, y = 0, z = 6.5; for 3, w = 15, x = 18, y = 3, z = 7.5; for 4, w = 15, x = 20, y = 6, z = 9.5; and for 5, w = 0, x = 3, y = 2, z = 3]. The molecular structure of these complexes reveals the presence of a monocationic hexanuclear derivative containing one perchlorate counteranion. The asymmetric unit of each of the hexanuclear derivatives comprises the dinuclear motif [NiLn(L)(?3-O)(?3-OH)(?-Piv)]. The cation contains three interlinked O-capped clusters: one Ln(III)3O and three Ni(II)Ln(III)2O. Each of the lanthanide centers is eight- coordinated (distorted trigonal-dodecahedron), while the nickel centers are hexacoordinate (distorted octahedral). The study of the magnetic properties of all compounds are reported and suggests single molecule magnet behavior for the Dy(III) derivative (1). PMID:25050753

Goura, Joydeb; Guillaume, Rogez; Rivière, Eric; Chandrasekhar, Vadapalli

2014-08-01

293

Substrate analogues for isoprenoid enzymes  

SciTech Connect

Diphosphonate analogues of geranyl diphosphate, resistant to degradation by phosphatases, were found to be alternate substrates for the reaction with farnesyl diphosphate synthetase isolated from avian liver. The difluoromethane analogue was shown to be the better alternate substrate, in agreement with solvolysis results which indicate that the electronegativity of the difluoromethylene unit more closely approximates that of the normal bridging oxygen. The usefulness of the C/sub 10/ difluoro analogue, for detecting low levels of isoprenoid enzymes in the presence of high levels of phosphatase activity, was demonstrated with a cell-free preparation from lemon peel. A series of C/sub 5/ through C/sub 15/ homoallylic and allylic diphosphonates, as well as two 5'-nucleotide diphosphonates, was prepared in high overall yield using the activation-displacement sequence. Radiolabeled samples of several of the allylic diphosphonates were prepared with tritium located at C1. A series of geraniols, stereospecifically deuterated at C1, was prepared. The enantiomeric purities and absolute configurations were determined by derivatization as the mandelate esters for analysis by /sup 1/H NMR. The stereochemistry of the activation-displacement sequence was examined using C1-deuterated substrates.

Stremler, K.E.

1987-01-01

294

Studies towards the total synthesis of Disorazole C1 and its analogues   

E-print Network

Structure–activity relationships (SARs) in the disorazole family have been revealed through the biological testing of natural disorazoles and their synthetic analogues, but little is known about the contribution of the ...

Ralston, Kevin John

2014-11-27

295

Synthesis and anti-tumor activity of carbohydrate analogues of the tetrahydrofuran containing acetogenins  

PubMed Central

The tetrahydrofuran (THF) containing annonaceous acetogenins (AAs) are attractive candidates for drug development because of their potent cytotoxicity against a wide range of tumors and their relatively simple and robust structures. Replacement of the THF segment with a sugar residue may deliver analogues with improved tumor selectivity and pharmacokinetics and are therefore attractive for drug development. As a first test to the feasibility of such structures, a set of such monosaccharide analogues was synthesized and assayed against four human tumor cell lines, cervical (HeLa), breast (MDA-MB231), T-cell leukemia (Jurkat) and prostate (PC-3). Certain analogues showed low micromolar activity that was comparable to a structurally similar, naturally occurring mono-THF acetogenin. A preliminary examination of the structure-activity profile of these carbohydrate analogues suggests that they have a similar mechanism of action as their THF congeners. PMID:24045006

Bachan, Stewart; Tony, K. A.; Kawamura, Akira; Montenegro, Diego; Joshi, Anjali; Garg, Himanshu; Mootoo, David R.

2013-01-01

296

Biodegradation of bisphenol A and its halogenated analogues by Cunninghamella elegans ATCC36112.  

PubMed

Bisphenol A and its halogenated analogues are commonly used industrial chemicals with strong toxicological effects over many organisms. In this study, metabolic fate of bisphenol A and its halogenated analogues were evaluated with Cunninghamella elegans ATCC36112. Bisphenol A and related analogues were rapidly transformed into several metabolites by C. elegans within 2-4 days. Detailed analysis of metabolites reveals that both phase I and II metabolism occurred in C. elegans. Cytochrome P450-dependent hydroxylation was observed in BPA. However, major reaction with bisphenol A and analogues with 1-2 halogen atoms were the formation of glucose-conjugate, not being inhibited by cytochrome P450 inhibitor. Overall metabolic rates decreased with increasing number of substitution at 2- and 6-position of BPA structures, which may be consequences of limited bioavailability or steric hindrance to conjugate-forming reaction. Information from the current study will provide detailed insights over the fungal metabolism of BPA and analogues. PMID:20455075

Keum, Young Soo; Lee, Hye Ri; Park, Hee Won; Kim, Jeong-Han

2010-11-01

297

Key Nutrients.  

ERIC Educational Resources Information Center

Lessons written to help trainer agents prepare aides for work with families in the Food and Nutrition Program are presented in this booklet. The key nutrients discussed in the 10 lessons are protein, carbohydrates, fat, calcium, iron, iodine, and Vitamins A, B, C, and D. the format of each lesson is as follows: Purpose, Presentation, Application…

Federal Extension Service (USDA), Washington, DC.

298

Synthesis and enzymatic studies of bisubstrate analogues for farnesyl diphosphate synthase.  

PubMed

Farnesyl diphosphate synthase catalyzes the sequential chain elongation reactions between isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) to form geranyl diphosphate (GPP) and between IPP and GPP to give farnesyl diphosphate (FPP). Bisubstrate analogues containing the allylic and homoallylic substrates were synthesized by joining fragments for IPP and the allylic diphosphates with a C-C bond between the methyl group at C3 in IPP and the Z-methyl group at C3 in DMAPP (3-OPP) and GPP (4-OPP), respectively. These constructs placed substantial limits on the conformational space available to the analogues relative to the two substrates. The key features of the synthesis of bisubstrate analogues 3-OPP and 4-OPP are a regioselective C-alkylation of the dianion of 3-methyl-3-buten-1-ol (5), a Z-selective cuprate addition of alkyl groups to an ?,?-alkynyl ester intermediate, and differential activation of allylic and homoallylic alcohols in the analogues, followed by a simultaneous displacement of the leaving groups with tris(tetra-n-butylammonium) hydrogen diphosphate to give the corresponding bisdiphosphate analogues. The bisubstrate analogues were substrates for FPP synthase, giving novel seven-membered ring analogues of GPP and FPP. The catalytic efficiencies for cyclization of 3-OPP and 4-OPP were similar to those for chain elongation with IPP and DMAPP. PMID:25734506

Ramamoorthy, Gurusankar; Pugh, Mark L; Tian, Bo-Xue; Phan, Richard M; Perez, Lawrence B; Jacobson, Matthew P; Poulter, C Dale

2015-04-17

299

Biological evaluation of a novel sorafenib analogue, t-CUPM.  

PubMed

Sorafenib (Nexavar®) is currently the only FDA-approved small molecule targeted therapy for advanced hepatocellular carcinoma. The use of structural analogues and derivatives of sorafenib has enabled the elucidation of critical targets and mechanism(s) of cell death for human cancer lines. We previously performed a structure-activity relationship study on a series of sorafenib analogues designed to investigate the inhibition overlap between the major targets of sorafenib Raf-1 kinase and VEGFR-2, and an enzyme shown to be a potent off-target of sorafenib, soluble epoxide hydrolase. In the current work, we present the biological data on our lead sorafenib analogue, t-CUPM, demonstrating that this analogue retains cytotoxicity similar to sorafenib in various human cancer cell lines and strongly inhibits growth in the NCI-60 cell line panel. Co-treatment with the pan-caspase inhibitor, Z-VAD-FMK, failed to rescue the cell viability responses of both sorafenib and t-CUPM, and immunofluorescence microscopy shows similar mitochondrial depolarization and apoptosis-inducing factor release for both compounds. These data suggest that both compounds induce a similar mechanism of caspase-independent apoptosis in hepatoma cells. In addition, t-CUPM displays anti-proliferative effects comparable to sorafenib as seen by a halt in G0/G1 in cell cycle progression. The structural difference between sorafenib and t-CUPM significantly reduces inhibitory spectrum of kinases by this analogue, and pharmacokinetic characterization demonstrates a 20-fold better oral bioavailability of t-CUPM than sorafenib in mice. Thus, t-CUPM may have the potential to reduce the adverse events observed from the multikinase inhibitory properties and the large dosing regimens of sorafenib. PMID:25413440

Wecksler, Aaron T; Hwang, Sung Hee; Liu, Jun-Yan; Wettersten, Hiromi I; Morisseau, Christophe; Wu, Jian; Weiss, Robert H; Hammock, Bruce D

2015-01-01

300

Synthesis and evaluation of heterocyclic analogues of bromoxynil.  

PubMed

One attractive strategy to discover more active and/or crop-selective herbicides is to make structural changes to currently registered compounds. This strategy is especially appealing for those compounds with limited herbicide resistance and whose chemistry is accompanied with transgenic tools to enable herbicide tolerance in crop plants. Bromoxynil is a photosystem II (PSII) inhibitor registered for control of broadleaf weeds in several agronomic and specialty crops. Recently at the University of Tennessee-Knoxville several analogues of bromoxynil were synthesized including a previously synthesized pyridine (2,6-dibromo-5-hydroxypyridine-2-carbonitrile sodium salt), a novel pyrimidine (4,6-dibromo-5-hydroxypyrimidine-2-carbonitrile sodium salt), and a novel pyridine N-oxide (2,6-dibromo-1-oxidopyridin-1-ium-4-carbonitrile). These new analogues of bromoxynil were also evaluated for their herbicidal activity on soybean (Glycine max), cotton (Gossypium hirsutum), redroot pigweed (Amaranthus retroflexus), velvetleaf (Abutilon theophrasti), large crabgrass (Digitaria sanguinalis), and pitted morningglory ( Ipomoea lacunose ) when applied at 0.28 kg ha(-1). A second study was conducted on a glyphosate-resistant weed (Amaranthus palmeri) with the compounds being applied at 0.56 kg ha(-1). Although all compounds were believed to inhibit PSII by binding in the quinone binding pocket of D1, the pyridine and pyridine-N-oxide analogues were clearly more potent than bromoxynil on Amaranthus retroflexus. However, application of the pyrimidine herbicide resulted in the least injury to all species tested. These variations in efficacy were investigated using molecular docking simulations, which indicate that the pyridine analogue may form a stronger hydrogen bond in the pocket of the D1 protein than the original bromoxynil. A pyridine analogue was able to control the glyphosate-resistant Amaranthus palmeri with >80% efficacy. The pyridine analogues of bromoxynil showed potential to have a different weed control spectrum compared to bromoxynil. A pyridine analogue of bromoxynil synthesized in this research controlled several weed species greater than bromoxynil itself, potentially due to enhanced binding within the PSII binding pocket. Future research should compare this analogue to bromoxynil using optimized formulations at higher application rates. PMID:24354444

Cutulle, Matthew A; Armel, Gregory R; Brosnan, James T; Best, Michael D; Kopsell, Dean A; Bruce, Barry D; Bostic, Heidi E; Layton, Donovan S

2014-01-15

301

Insight into the binding mode between HIV-1 integrase and pyrimidone analogue inhibitors with MD simulation and 3D-QSAR.  

PubMed

HIV-1 integrase (HIVIN) plays a key role in the replication of the HIV-1 virus and represents an attractive target for anti-HIV drug design. Experimental observation suggests that pyrimidone analogues have potent anti-HIV activity. Then, we modeled an HIVIN catalytic core domain based on the crystal structure of the prototype foamy virus (PFV) integrase. Molecular docking and molecular dynamics simulations were used to investigate the interaction mechanism between pyrimidone analogues and the HIVIN catalytic core domain. MD results suggest that the most active molecule (6K) has more stable hydrogen bonds and hydrophobic contacts than the FDA approved anti-HIV drug Raltegravir. Furthermore, the analogues and Raltegravir might have similar binding modes with HIVIN. Finally, Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) methods were used to construct three dimensional quantitative structure-activity (3D-QSAR) models. Eleven test set compounds which are not included in the training set were used to evaluate these models. The results suggest that these models are robust and have good prediction abilities. PMID:23210925

Ma, Songyao; Ye, Wei; Ji, Dingjue; Chen, Hai-Feng

2013-05-01

302

POLYCHLORINATED BIPHENYLS AS HORMONALLY ACTIVE STRUCTURAL ANALOGUES  

EPA Science Inventory

Among the environmental chemicals believed to have the potential to disrupt the endocrine systems of animals including humans, the polychlorinated biphenyls are a chemical class of considerable concern. Possible mechanisms by which these chemicals may interfere with endocrine fun...

303

Cysteine analogues potentiate glucose-induced insulin release in vitro  

SciTech Connect

In rat pancreatic islets, cysteine analogues, including glutathione, acetylcysteine, cysteamine, D-penicillamine, L-cysteine ethyl ester, and cysteine-potentiated glucose (11.1 mM) induced insulin secretion in a concentration-dependent manner. Their maximal effects were similar and occurred at approximately 0.05, 0.05, 0.1, 0.5, 1.0, 1.0 mM, respectively. At substimulatory glucose levels (2.8 mM), insulin release was not affected by these compounds. In contrast, thiol compounds, structurally different from cysteine and its analogues, such as mesna, tiopronin, meso-2,3-dimercaptosuccinic acid (DMSA), dimercaprol (BAL), beta-thio-D-glucose, as well as those cysteine analogues that lack a free-thiol group, including L-cystine, cystamine, D-penicillamine disulfide, S-carbocysteine, and S-carbamoyl-L-cysteine, did not enhance insulin release at stimulatory glucose levels (11.1 mM); cystine (5 mM) was inhibitory. These in vitro data indicate that among the thiols tested here, only cysteine and its analogues potentiate glucose-induced insulin secretion, whereas thiols that are structurally not related to cysteine do not. This suggests that a cysteine moiety in the molecule is necessary for the insulinotropic effect. For their synergistic action to glucose, the availability of a sulfhydryl group is also a prerequisite. The maximal synergistic action is similar for all cysteine analogues tested, whereas the potency of action is different, suggesting similarity in the mechanism of action but differences in the affinity to the secretory system.

Ammon, H.P.; Hehl, K.H.; Enz, G.; Setiadi-Ranti, A.; Verspohl, E.J.

1986-12-01

304

Template polymerization of nucleotide analogues  

NASA Technical Reports Server (NTRS)

Recent work on the template-directed reactions of the natural D-nucleotides has made it clear that l-nucleotides and nucleotide-like derivatives of other sugars would strongly inhibit the formation of long oligonucleotides. Consequently, attention is focusing on molecules simpler than nucleotides that might have acted as monomers of an information transfer system. We have begun a general exploration of the template directed reactions of diverse peptide analogues. I will present work by Dr. Taifeng Wu on oxidative oligomerization of phosphorothioates and of Dr. Mary Tohidi on the cyclic polymerization of nucleoside and related cyclic pyrophosphates.

Orgel, L. E.

1991-01-01

305

Key Structural Features of the Actin Filament Arp2/3 Complex Branch Junction Revealed by Molecular Simulation  

PubMed Central

We investigated the structure, properties and dynamics of the actin filament branch junction formed by Arp2/3 complex using all-atom molecular dynamics simulations based on a model fit to a reconstruction from electron tomograms. Simulations of the entire structure consisting of 31 protein subunits together with solvent molecules contained ~3 million atoms were performed for an aggregate time of 175 ns. One 75 ns simulation of the original reconstruction was compared to two 50 ns simulations of alternate structures, showing that the hypothesized branch junction structure is very stable. Our simulations revealed that the interface between Arp2/3 complex and the mother actin filament features a large number of salt bridges and hydrophobic contacts, many of which are dynamic and formed/broken on the timescale of the simulation. The simulations suggest that the DNase binding loops in Arp3, and possibly Arp2, form stabilizing contacts with the mother filament. Unbiased comparison of models sampled from the MD simulation trajectory with the primary experimental electron tomography data identified regions were snapshots from the simulation provide atomic details of the model structures and also pinpoints regions where the initial modeling based on the electron tomogram reconstruction may be sub-optimal. PMID:22206989

Pfaendtner, Jim; Volkmann, Niels; Hanein, Dorit; Dalhaimer, Paul; Pollard, Thomas D.; Voth, Gregory A.

2012-01-01

306

Molecular modeling of Congo Red analogues containing terphenyl and quarterphenyl moieties  

Microsoft Academic Search

The molecular structures of Congo Red and its terphenyl and quarterphenyl analogues were optimized by applying AM1 and PM3 semiempirical methods to partially optimized starting structures. It was necessary to carry out repetitive sequences consisting of manual adjustments to the input structures followed by optimization, in order to locate minima in each structure. In addition, the conformational space associated with

Jason Lye; Harold S. Freeman; Russell D. Cox

2000-01-01

307

Rational design of ?-helix-stabilized exendin-4 analogues.  

PubMed

Exendin-4 (Ex4) is a potent glucagon-like peptide-1 receptor agonist, a drug regulating the plasma glucose level of patients suffering from type 2 diabetes. The molecule's poor solubility and its readiness to form aggregates increase the likelihood of unwanted side effects. Therefore, we designed Ex4 analogues with improved structural characteristics and better water solubility. Rational design was started from the parent 20-amino acid, well-folded Trp cage (TC) miniprotein and involved the step-by-step N-terminal elongation of the TC head, resulting in the 39-amino acid Ex4 analogue, E19. Helical propensity coupled to tertiary structure compactness was monitored and quantitatively analyzed by electronic circular dichroism and nuclear magnetic resonance (NMR) spectroscopy for the 14 peptides of different lengths. Both (15)N relaxation- and diffusion-ordered NMR measurements were established to investigate the inherent mobility and self-association propensity of Ex4 and E19. Our designed E19 molecule has the same tertiary structure as Ex4 but is more helical than Ex4 under all studied conditions; it is less prone to oligomerization and has preserved biological activity. These conditions make E19 a perfect lead compound for further drug discovery. We believe that this structural study improves our understanding of the relationship between local molecular features and global physicochemical properties such as water solubility and could help in the development of more potent Ex4 analogues with improved pharmacokinetic properties. PMID:24828921

Rovó, Petra; Farkas, Viktor; Stráner, Pál; Szabó, Mária; Jermendy, Agnes; Hegyi, Orsolya; Tóth, Gábor K; Perczel, András

2014-06-10

308

Analogue gravity in hyperbolic metamaterials  

E-print Network

Sub-wavelength confinement of light in nonlinear hyperbolic metamaterials due to formation of spatial solitons has attracted much recent attention because of its seemingly counter-intuitive behavior. In order to achieve self-focusing in a hyperbolic wire medium, a nonlinear self-defocusing Kerr medium must be used as a dielectric host. Here we demonstrate that this behavior finds natural explanation in terms of analogue gravity. Wave equation describing propagation of extraordinary light inside hyperbolic metamaterials exhibits 2+1 dimensional Lorentz symmetry. The role of time in the corresponding effective 3D Minkowski spacetime is played by the spatial coordinate aligned with the optical axis of the metamaterial. Nonlinear optical Kerr effect bends this spacetime resulting in effective gravitational force between extraordinary photons. In order for the effective gravitational constant to be positive, negative self-defocusing Kerr medium must be used as a host. If gravitational self-interaction is strong enough, spatial soliton may collapse into a black hole analogue.

Igor I. Smolyaninov

2013-09-09

309

The Valles natural analogue project  

SciTech Connect

The contact between an obsidian flow and a steep-walled tuff canyon was examined as an analogue for a highlevel waste repository. The analogue site is located in the Valles Caldera in New Mexico, where a massive obsidian flow filled a paleocanyon in the Battleship Rock tuff. The obsidian flow provided a heat source, analogous to waste panels or an igneous intrusion in a repository, and caused evaporation and migration of water. The tuff and obsidian samples were analyzed for major and trace elements and mineralogy by INAA, XRF, X-ray diffraction; and scanning electron microscopy and electron microprobe. Samples were also analyzed for D/H and {sup 39}Ar/{sup 4O} isotopic composition. Overall,the effects of the heating event seem to have been slight and limited to the tuff nearest the contact. There is some evidence of devitrification and migration of volatiles in the tuff within 10 meters of the contact, but variations in major and trace element chemistry are small and difficult to distinguish from the natural (pre-heating) variability of the rocks.

Stockman, H.; Krumhansl, J.; Ho, C. [Sandia National Labs., Albuquerque, NM (United States); McConnell, V. [Alaska Univ., Fairbanks, AK (United States). Geophysical Inst.

1994-12-01

310

Demonstration of the in vivo interaction of key cell death regulators by structure-based design of  

E-print Network

release of CED-4 from CED-4 CED-9 complexes. Based on a mod- eled EGL-1 CED-9 complex structure, we169E) and EGL-1-induced release of CED-4 from CED-4 CED-9(G169E) complexes. Importantly establish that direct physical inter- action between EGL-1 and CED-9 is essential for the release of CED-4

Xue, Ding

311

The Simulation and Optimal Design of Key Structure on Shellside of Large Heat Exchanger with Longitudinal Flow of Shellside Fluid  

Microsoft Academic Search

In the paper, the periodic unit duct model is built for large heat exchanger with longitudinal flow of shellside fluid according to its structural characteristic. By employing CFD software FLUENT, the numerical simulation of models under different media, different Re number and different rod-baffle pitch are carried out. And the detailed characteristics of fluid flow and heat transfer in the

QI-WU DONG; MIN-SHAN LIU; XIAO-DONG ZHAO

312

Hippocampal Structure and Human Cognition: Key Role of Spatial Processing and Evidence Supporting the Efficiency Hypothesis in Females  

ERIC Educational Resources Information Center

Here we apply a method for automated segmentation of the hippocampus in 3D high-resolution structural brain MRI scans. One hundred and four healthy young adults completed twenty one tasks measuring abstract, verbal, and spatial intelligence, along with working memory, executive control, attention, and processing speed. After permutation tests…

Colom, Roberto; Stein, Jason L.; Rajagopalan, Priya; Martinez, Kenia; Hermel, David; Wang, Yalin; Alvarez-Linera, Juan; Burgaleta, Miguel; Quiroga, Ma. Angeles; Shih, Pei Chun; Thompson, Paul M.

2013-01-01

313

Synthesis and Bioactivity of ?-Substituted Fosmidomycin Analogues Targeting 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase.  

PubMed

Blocking the 2-C-methyl-d-erythrithol-4-phosphate (MEP) pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting Plasmodium or Mycobacterium spp. growth. Fosmidomycin (1) and its homologue FR900098 (2) potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this pathway. Here we introduced aryl or aralkyl substituents at the ?-position of the hydroxamate analogue of 2. While direct addition of a ?-aryl moiety resulted in poor inhibition, longer linkers between the carbon backbone and the phenyl ring were generally associated with better binding to the enzymes. X-ray structures of the parasite Dxr-inhibitor complexes show that the "longer" compounds generate a substantially different flap structure, in which a key tryptophan residue is displaced, and the aromatic group of the ligand lies between the tryptophan and the hydroxamate's methyl group. Although the most promising new Dxr inhibitors lack activity against Escherichia coli and Mycobacterium smegmatis, they proved to be highly potent inhibitors of Plasmodium falciparum in vitro growth. PMID:25781377

Chofor, René; Sooriyaarachchi, Sanjeewani; Risseeuw, Martijn D P; Bergfors, Terese; Pouyez, Jenny; Johny, Chinchu; Haymond, Amanda; Everaert, Annelien; Dowd, Cynthia S; Maes, Louis; Coenye, Tom; Alex, Alexander; Couch, Robin D; Jones, T Alwyn; Wouters, Johan; Mowbray, Sherry L; Van Calenbergh, Serge

2015-04-01

314

Mechanism of Carboxypeptidase A: Hydration of a Ketonic Substrate Analogue  

Microsoft Academic Search

The structure of the complex between carboxypeptidase Aalpha (EC 3.4.17.1) and the ketonic substrate analogue 5-benzamido-2-benzyl-4-oxopentanoic acid (BOP) has been determined by x-ray crystallographic methods to a resolution of 1.7 angstrom (final R = 0.191). Interestingly, BOP was observed to bind to the active site of carboxypeptidase Aalpha as the covalent hydrate adduct. Because BOP is probably less than 0.2%

David W. Christianson; Peter R. David; William N. Lipscomb

1987-01-01

315

Marine Pyrrolocarbazoles and Analogues: Synthesis and Kinase Inhibition  

PubMed Central

Granulatimide and isogranulatimide are alkaloids obtained from marine sources which have been shown to inhibit cell-cycle G2-checkpoint, targeting more particularly checkpoint 1 kinase (Chk1). At a structural level, they possess a characteristic pyrrolocarbazole framework also shared by the well-known rebeccamycin and staurosporine microbial metabolites which have been described to inhibit topoisomerase I and diverse kinases, respectively. This review reports precisely on the synthesis and kinase inhibitory activities of pyrrolocarbazole-based analogues of granulatimide. PMID:20098609

Deslandes, Sébastien; Chassaing, Stefan; Delfourne, Evelyne

2009-01-01

316

Endiandric Acid Analogues from the Roots of Beilschmiedia erythrophloia.  

PubMed

Investigation of the roots of Beilschmiedia erythrophloia has led to the isolation of seven new endiandric acid analogues, erythrophloins A-F (1-6) and beilcyclone A (7), together with 11 known compounds. The structures of 1-7 were determined using spectroscopic techniques. Two constituents, erythrophloin C (3) and suberosol B (8), exhibited antitubercular activity against Mycobacterium tuberculosis H37Rv, showing MIC values of 50 and 28.9 microg/mL, respectively. PMID:19072217

Yang, Ping-Shin; Cheng, Ming-Jen; Peng, Chien-Fang; Chen, Jih-Jung; Chen, Ih-Sheng

2009-01-01

317

Structure of Importin13–Ubc9 complex: nuclear import and release of a key regulator of sumoylation  

PubMed Central

Importin13 (Imp13) is an unusual ?-karyopherin that is able to both import and export cargoes in and out of the nucleus. In the cytoplasm, Imp13 associates with different cargoes such as Mago-Y14 and Ubc9, and facilitates their import into the nucleus where RanGTP binding promotes the release of the cargo. In this study, we present the 2.8 Å resolution crystal structure of Imp13 in complex with the SUMO E2-conjugating enzyme, Ubc9. The structure shows an uncommon mode of cargo–karyopherin recognition with Ubc9 binding at the N-terminal portion of Imp13, occupying the entire RanGTP-binding site. Comparison of the Imp13–Ubc9 complex with Imp13–Mago-Y14 shows the remarkable plasticity of Imp13, whose conformation changes from a closed ring to an open superhelix when bound to the two different cargoes. The structure also shows that the binding mode is compatible with the sumoylated states of Ubc9. Indeed, we find that Imp13 is able to bind sumoylated Ubc9 in vitro and suppresses autosumoylation activity in the complex. PMID:21139563

Grünwald, Marlene; Bono, Fulvia

2011-01-01

318

Structure of Importin13-Ubc9 complex: nuclear import and release of a key regulator of sumoylation.  

PubMed

Importin13 (Imp13) is an unusual ?-karyopherin that is able to both import and export cargoes in and out of the nucleus. In the cytoplasm, Imp13 associates with different cargoes such as Mago-Y14 and Ubc9, and facilitates their import into the nucleus where RanGTP binding promotes the release of the cargo. In this study, we present the 2.8 Å resolution crystal structure of Imp13 in complex with the SUMO E2-conjugating enzyme, Ubc9. The structure shows an uncommon mode of cargo-karyopherin recognition with Ubc9 binding at the N-terminal portion of Imp13, occupying the entire RanGTP-binding site. Comparison of the Imp13-Ubc9 complex with Imp13-Mago-Y14 shows the remarkable plasticity of Imp13, whose conformation changes from a closed ring to an open superhelix when bound to the two different cargoes. The structure also shows that the binding mode is compatible with the sumoylated states of Ubc9. Indeed, we find that Imp13 is able to bind sumoylated Ubc9 in vitro and suppresses autosumoylation activity in the complex. PMID:21139563

Grünwald, Marlene; Bono, Fulvia

2011-01-19

319

Contact zones and hydrothermal systems as analogues to repository conditions  

SciTech Connect

Radioactive waste isolation efforts in the US are currently focused on examining basalt, tuff, salt, and crystalline rock as candidate rock types to encompass waste repositories. As analogues to near-field conditions, the distributions of radio- and trace-elements have been examined across contacts between these rocks and dikes and stocks that have intruded them. The intensive study of the Stripa quartz monzonite has also offered the opportunity to observe the distribution of uranium and its daughters in groundwater and its relationship to U associated with fracture-filling and alteration minerals. Investigations of intrusive contact zones to date have included (1) a tertiary stock into Precambrian gneiss, (2) a stock into ash flow tuff, (3) a rhyodacite dike into Columbia River basalt, and (4) a kimberlite dike into salt. With respect to temperature and pressure, these contact zones may be considered "worst-case scenario" analogues. Results indicate that there has been no appreciable migration of radioelements from the more radioactive intrusives into the less radioactive country rocks, either in response to the intrusions or in the fracture-controlled hydrological systems that developed following emplacement. In many cases, the radioelements are locked up in accessory minerals, suggesting that artificial analogues to these would make ideal waste forms. Emphasis should now shift to examination of active hydrothermal systems, studying the distribution of key elements in water, fractures, and alteration minerals under pressure and temperature conditions most similar to those expected in the near-field environment of a repository. 14 refs.

Wollenberg, H.A.; Flexser, S.

1984-10-01

320

Surface and Moho topography as key constraints for understanding the thermo-rheological structure and longevity of cratons and tectons  

NASA Astrophysics Data System (ADS)

Surface topography and Moho are the most robust observables that have been insufficiently exploited for containing the rheological and thermal structure and hence for understanding the longevity and eventual destruction of cratons and 'tectons'. Craton longevity has been often explained by their buoyancy and analysed by testing gravitational stability of cratonic mantle 'keels' as a function of the hypothesized plate thickness and thermo-rheological structure. Destruction of some cratons (e.g. North China) and data indicating little if no buoyancy of some tectons (e.g., Arabian shield) suggest that buoyancy is not the only factor of their stability, and previous studies show that their mechanical strength is as important as buoyancy. The upper bounds on this strength are provided by flexural studies demonstrating that Te values (equivalent elastic thickness) in cratons are highest in the world and may probably reach 150 km. Yet, the sensitivity of common methods is poor for Te values above 80 km while the lower bounds on the strength and the equivalent elastic thickness of cratons are still matter of debate. How this strength is partitioned between crust and mantle, and which set of rheological parameters pertain, remain major unknowns. We show that smooth low topography and 'frozen' heterogeneous crustal structure of cratons represent the missing constraints for understanding of craton longevity. The cratonic crust is characterized by isostatically misbalanced density heterogeneities, suggesting that the lithosphere has to be strong enough to keep them 'frozen' through the time without producing major gravitational instabilities and topographic undulations. Hence, to constrain thermo-rheological properties of cratons one should first investigate the stability of their topography and internal structure (constrained from seismic and gravity data). Our thermo-mechanical numerical experiments accounting for free surface boundary condition demonstrate that craton stability cannot be warranted by crustal strength only, and that strong dry olivine mantle rheology and cold thick lithosphere are needed for craton survival. We find fairly robust lower-bound limits on their thermo-rheological structure. In particular, the minimal Te needed for long-term stability of continents (cratons or tectons) is approximately 70 km.

Burov, E. B.; Francois, T.

2013-12-01

321

Transition States and transition state analogue interactions with enzymes.  

PubMed

Enzymatic transition states have lifetimes of a few femtoseconds (fs). Computational analysis of enzyme motions leading to transition state formation suggests that local catalytic site motions on the fs time scale provide the mechanism to locate transition states. An experimental test of protein fs motion and its relation to transition state formation can be provided by isotopically heavy proteins. Heavy enzymes have predictable mass-altered bond vibration states without altered electrostatic properties, according to the Born-Oppenheimer approximation. On-enzyme chemistry is slowed in most heavy proteins, consistent with altered protein bond frequencies slowing the search for the transition state. In other heavy enzymes, structural changes involved in reactant binding and release are also influenced. Slow protein motions associated with substrate binding and catalytic site preorganization are essential to allow the subsequent fs motions to locate the transition state and to facilitate the efficient release of products. In the catalytically competent geometry, local groups move in stochastic atomic motion on the fs time scale, within transition state-accessible conformations created by slower protein motions. The fs time scale for the transition state motions does not permit thermodynamic equilibrium between the transition state and stable enzyme states. Isotopically heavy enzymes provide a diagnostic tool for fast coupled protein motions to transition state formation and mass-dependent conformational changes. The binding of transition state analogue inhibitors is the opposite in catalytic time scale to formation of the transition state but is related by similar geometries of the enzyme-transition state and enzyme-inhibitor interactions. While enzymatic transition states have lifetimes as short as 10(-15) s, transition state analogues can bind tightly to enzymes with release rates greater than 10(3) s. Tight-binding transition state analogues stabilize the rare but evolved enzymatic geometry to form the transition state. Evolution to efficient catalysis optimized this geometry and its stabilization by a transition state mimic results in tight binding. Release rates of transition state analogues are orders of magnitude slower than product release in normal catalytic function. During catalysis, product release is facilitated by altered chemistry. Compared to the weak associations found in Michaelis complexes, transition state analogues involve strong interactions related to those in the transition state. Optimum binding of transition state analogues occurs when the complex retains the system motions intrinsic to transition state formation. Conserved dynamic motion retains the entropic components of inhibitor complexes, improving the thermodynamics of analogue binding. PMID:25848811

Schramm, Vern L

2015-04-21

322

CO2 Capture with Enzyme Synthetic Analogue  

SciTech Connect

Overview of an ongoing, 2 year research project partially funded by APRA-E to create a novel, synthetic analogue of carbonic anhydrase and incorporate it into a membrane for removal of CO2 from flue gas in coal power plants. Mechanism background, preliminary feasibility study results, molecular modeling of analogue-CO2 interaction, and program timeline are provided.

Harry Cordatos

2010-11-08

323

Synthesis and cytotoxicity assay of four ganglioside GM3 analogues.  

PubMed

A concise and efficient synthetic route for preparation of four ganglioside GM3 analogues was described. The key step is a highly regioselective and stereoselective ?-sialylation from a suitably protected glycoside acceptor with a sialyl xanthate to provide the sialo-oligosaccharide in good yield. The cytotoxic properties of the synthetic gangliosides were evaluated against normal human keratinocytes and human HCT116 and K562 cancer cells. Two of them exhibited good antiproliferative activity and displayed a better cytotoxicity against cancer cell than HaCaT normal cell. PMID:24534540

Qu, Huanhuan; Liu, Jian-Miao; Wdzieczak-Bakala, Joanna; Lu, Dan; He, Xianran; Sun, Wenji; Sollogoub, Matthieu; Zhang, Yongmin

2014-03-21

324

Towards bottom-up nanopatterning of Prussian blue analogues  

PubMed Central

Summary Ordered nanoperforated TiO2 monolayers fabricated through sol–gel chemistry were used to grow isolated particles of Prussian blue analogues (PBA). The elaboration of the TiO2/CoFe PBA nanocomposites involves five steps. The samples were characterized by scanning electron microscopy (SEM), atomic force microscopy (AFM), infrared spectroscopy and X-ray photoelectron spectroscopy (XPS) all along the synthesis process. Selected physico-chemical parameters have been varied in order to determine the key steps of the synthesis process and to optimize it. This study is an important step towards the full control of the fabrication process. PMID:25383305

Trannoy, Virgile; Faustini, Marco; Grosso, David; Mazerat, Sandra; Brisset, François; Dazzi, Alexandre

2014-01-01

325

Astrobiology Field Research in Moon/Mars Analogue Environments: Preface  

NASA Technical Reports Server (NTRS)

Extreme environments on Earth often provide similar terrain conditions to landing/operation sites on Moon and Mars. Several field campaigns (EuroGeoMars2009 and DOMMEX/ILEWG EuroMoonMars from November 2009 to March 2010) were conducted at the Mars Desert Research Station (MDRS) in Utah. Some of the key astrobiology results are presented in this special issue on Astrobiology field research in Moon/Mars analogue environments relevant to investigate the link between geology, minerals, organics and biota. Preliminary results from a multidisciplinary field campaign at Rio Tinto in Spain are presented.

Foing, B. H.; Stoker, C.; Ehrenfreund, P.

2011-01-01

326

Astrobiology field research in Moon/Mars analogue environments  

NASA Astrophysics Data System (ADS)

Extreme environments on Earth often provide similar terrain conditions to landing/operation sites on Moon and Mars. Several field campaigns (EuroGeoMars2009 and DOMMEX/ILEWG EuroMoonMars from November 2009 to March 2010) were conducted at the Mars Desert Research Station (MDRS) in Utah. Some of the key astrobiology results are presented in this special issue on ‘Astrobiology field research in Moon/Mars analogue environments’ relevant to investigate the link between geology, minerals, organics and biota. Preliminary results from a multidisciplinary field campaign at Rio Tinto in Spain are presented.

Foing, B. H.; Stoker, C.; Ehrenfreund, P.

2011-07-01

327

The Biostructural Features of Additional Jasplakinolide (Jaspamide) Analogues  

PubMed Central

The cyclodepsipeptide jasplakinolide (1) (a.k.a. jaspamide), isolated previously from the marine sponge Jaspis splendens, is a unique cytotoxin and molecular probe that operates through stabilization of filamentous actin (F-actin). We have recently disclosed that two analogues of 1, jasplakinolides B (3) and E, were referred to the National Cancer Institute's (NCI) Biological Evaluation Committee and the objective of this study was to re-investigate a Fijian collection of J. splendens in an effort to find jasplakinolide congeners with similar biological properties. The current efforts have afforded six known jasplakinolide analogues (4 - 7, 9 - 10), two structures requiring revision (8 and 14) and four new congeners of 1 (11 - 13, 15) including open chain derivatives and structures with modified ?-tyrosine residues. Compounds were evaluated for biological activity in the NCI's 60 cell line screen and in a microfilament disruption assay in both HCT-116 and HeLa cells. These two phenotypic screens provide evidence that each cytotoxic analogue, including jasplakinolide B (3), operates by modification of microfilaments. The new structure jasplakinolide V (13) has also been selected for study by the NCI's Biological Evaluation Committee. In addition, the results of a clonogenic dose response study on jasplakinolide are presented. PMID:21241058

Watts, Katharine R.; Morinaka, Brandon I.; Amagata, Taro; Robinson, Sarah J.; Tenney, Karen; Bray, Walter M.; Gassner, Nadine C.; Lokey, R. Scott; Media, Joseph; Valeriote, Frederick A.; Crews, Phillip

2011-01-01

328

Secondary structure of the rRNA ITS2 region reveals key evolutionary patterns in acroporid corals.  

PubMed

This study investigates the ribosomal RNA transcript secondary structure in corals as confirmed by compensatory base changes in Isopora/Acropora species. These species are unique versus all other corals in the absence of a eukaryote-wide conserved structural component, the helix III in internal transcriber spacer (ITS) 2, and their variability in the 5.8S-LSU helix basal to ITS2, a helix with pairings identical among all other scleractinian corals. Furthermore, Isopora/Acropora individuals display at least two, and as many as three, ITS sequence isotypes in their genome which appear to be capable of function. From consideration of the conserved elements in ITS2 and flanking regions, it appears that there are three major groups within the IsoporaAcropora lineage: the Isopora + Acropora "longi" group, the large group including Caribbean Acropora + the Acropora "carib" types plus the bulk of the Indo-Pacific Acropora species, and the remaining enigmatic "pseudo" group found in the Pacific. Interbreeding is possible among Caribbean A. palmata and A. cervicornis and among some species of Indo-Pacific Acropora. Recombinant ITS sequences are obvious among these latter, such that morphology (as represented by species name) does not correlate with common ITS sequence. The combination of characters revealed by RNA secondary structure analyses suggests a recent past/current history of interbreeding among the Indo-Pacific Acropora species and a shared ancestry of some of these with the Caribbean Acropora. The unusual absence of helix III of ITS2 of Isopora/Acropora species may have some causative role in the equally unusual instability in the 5.8S-LSU helix basal to ITS2 of this species complex. PMID:18781354

Coleman, Annette W; van Oppen, Madeleine J H

2008-10-01

329

Antifouling Activity of Bromotyrosine-Derived Sponge Metabolites and Synthetic Analogues  

Microsoft Academic Search

Eighteen brominated sponge-derived metabolites and synthetic analogues were analyzed for antilarval settlement of Balanus improvisus. Only compounds exhibiting oxime substituents including bastadin-3 (4), ?4 (1), ?9 (2), and ?16 (3), hemibastadin-1 (6), aplysamine-2 (5), and psammaplin A (10) turned out to inhibit larval settling at 1 to 10 ?M. Analogues of hemibastadin-1 (6) were synthesized and tested for structure activity studies.

Sofia Ortlepp; Martin Sjögren; Mia Dahlström; Horst Weber; Rainer Ebel; RuAngelie Edrada; Carsten Thoms; Peter Schupp; Lars Bohlin; Peter Proksch

2007-01-01

330

Quinlobelane: A water-soluble lobelane analogue and inhibitor of VMAT2  

PubMed Central

Replacing the phenyl groups in the structure of the VMAT2 inhibitor, lobelane with either pyridyl, quinolyl or indolyl groups affords novel analogues with improved water solubility. The synthetic methodologies reported herein also underscore the paucity of hydrogenation methods that offer selectivity in the synthesis of the different classes of heteroaromatic lobelane analogues. The quinolyl group was the only replacement for the phenyl group in lobelane that retained VMAT2 inhibition. PMID:20494575

Vartak, Ashish P.; Deaciuc, A. Gabriela; Dwoskin, Linda P.; Crooks, Peter A.

2013-01-01

331

Variation effect on the insecticide activity of DDT analogues. A chemometric approach  

NASA Astrophysics Data System (ADS)

We investigated a variation effect on the insecticide activity of DDT analogues by using the first principles electronic structure calculations and the neural network analysis. It has been found that the charge distribution at the specific atomic sites in the DDT molecule is related to their toxicity. This approach can contribute to designing a new insecticide and a new harmlessness process of the DDT analogues.

Itoh, S.; Nagashima, U.

2002-08-01

332

Crystal Structure Analysis of Human Glutamine : Fructose 6-Phosphate Amidotransferase, a Key Regulator in Type 2 Diabetes  

NASA Astrophysics Data System (ADS)

Glutamine : fructose 6-phosphate amidotransferase (GFAT) is a rate-limiting enzyme in the hexoamine biosythetic pathway and plays an important role in type 2 diabetes. We now report the first structures of the isomerase domain of the human GFAT in the presence of cyclic glucose 6-phosphate and linear glucosamine 6-phosphate. The C-terminal tail including the active site displays a rigid conformation, similar to the corresponding Escherichia coli enzyme. The diversity of the CF helix near the active site suggests the helix is a major target for drug design. Our study provides insights into the development of therapeutic drugs for type 2 diabetes.

Nakaishi, Yuichiro; Bando, Masahiko

333

Key microstructures controlling the mechanical properties of two-phase TiAl alloys with lamellar structures  

SciTech Connect

TiAl alloys with the base composition of Ti-47Al-2Cr-2Nb (at.%) were prepared by arc melting and drop casting, followed by hot extrusion above the {alpha}-transus temperature, T{sub {alpha}}. The hot extruded materials were then heat treated above and below T{sub {alpha}} in order to control microstructural features in these lamellar structures. Mechanical properties of these alloys were determined by tensile testing at temperatures to 1000 C. Tensile elongation at room temperature (RT) is strongly dependent on grain size, showing increased ductility with decreasing grain size. Strength at RT and elevated temperatures is sensitive to interlamellar spacing, showing increased strength with decreasing lamellar spacing. Hall-Petch relations hold well for yield strength at RT and elevated temperatures and for tensile elongation at RT. Tensile elongations of about 5% and yield strengths around 900 MPa are achieved by controlling both colony size and interlamellar spacing. Mechanical properties of the TiAl alloys with controlled lamellar structures produced directly by hot extrusion are much superior to those produced by conventional thermomechanical treatments.

Liu, C.T.; Maziasz, P.J.; Wright, J.L.

1996-12-31

334

Stepwise Organization of the ?-Structure Identifies Key Regions Essential for the Propagation and Cytotoxicity of Insulin Amyloid Fibrils*  

PubMed Central

Amyloid fibrils are supramolecular assemblies, the deposition of which is associated with many serious diseases including Alzheimer, prion, and Huntington diseases. Several smaller aggregates such as oligomers and protofibrils have been proposed to play a role in early stages of the fibrillation process; however, little is known about how these species contribute to the formation of mature amyloid fibrils with a rigid cross-? structure. Here, we identified a new pathway for the formation of insulin amyloid fibrils at a high concentration of salt in which mature fibrils were formed in a stepwise manner via a prefibrillar intermediate: minute prefibrillar species initially accumulated, followed by the subsequent formation of thicker amyloid fibrils. Fourier transform infrared spectra suggested the sequential formation of two types of ?-sheets with different strength hydrogen bonds, one of which was developed concomitantly with the mutual assembly of the prefibrillar intermediate to form mature fibrils. Interestingly, fibril propagation and cellular toxicity appeared only after the later step of structural organization, and a comparison of ?-sheet regions between the prefibrillar intermediate and mature fibrils using proteolysis led to the proposal of specific regions essential for manifestation of these properties. PMID:24569992

Chatani, Eri; Imamura, Hiroshi; Yamamoto, Naoki; Kato, Minoru

2014-01-01

335

A First Principles Density-Functional Calculation of the Electronic and Vibrational Structure of the Key Melanin Monomers  

E-print Network

We report first principles density functional calculations for hydroquinone (HQ), indolequinone (IQ) and semiquinone (SQ). These molecules are believed to be the basic building blocks of the eumelanins, a class of bio-macromolecules with important biological functions (including photoprotection) and with potential for certain bioengineering applications. We have used the DeltaSCF (difference of self consistent fields) method to study the energy gap between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO), Delta_HL. We show that Delta_HL is similar in IQ and SQ but approximately twice as large in HQ. This may have important implications for our understanding of the observed broad band optical absorption of the eumelanins. The possibility of using this difference in Delta_HL to molecularly engineer the electronic properties of eumelanins is discussed. We calculate the infrared and Raman spectra of the three redox forms from first principles. Each of the molecules have significantly different infrared and Raman signatures, and so these spectra could be used in situ to non-destructively identify the monomeric content of macromolecules. It is hoped that this may be a helpful analytical tool in determining the structure of eumelanin macromolecules and hence in helping to determine the structure-property-function relationships that control the behaviour of the eumelanins.

B. J. Powell; T. Baruah; N. Bernstein; K. Brake; Ross H. McKenzie; P. Meredith; M. R. Pederson

2004-01-23

336

Synthesis, biological activity, and conformational study of N-methylated allatostatin analogues inhibiting juvenile hormone biosynthesis.  

PubMed

An allatostatin (AST) neuropeptide mimic (H17) is a potential insect growth regulator, which inhibits the production of juvenile hormone (JH) by the corpora allata. To determine the effect of conformation of novel AST analogues and their ability to inhibit JH biosynthesis, eight insect AST analogues were synthesized using H17 as the lead compound by N-methylation scanning, which is a common strategy for improving the biological properties of peptides. A bioassay using JH production by corpora allata of the cockroach Diploptera punctata indicated that single N-methylation mimics (analogues 1-4) showed more activity than double N-methylation mimics (analogues 5-8). Especially, analogues 1 and 4 showed roughly equivalent activity to that of H17, with IC50 values of 5.17 × 10(-8) and 6.44 × 10(-8) M, respectively. Molecular modeling based on nuclear magnetic resonance data showed that the conformation of analogues 1 and 4 seems to be flexible, whereas analogues 2 and 3 showed a type IV ?-turn. This flexible linear conformation was hypothesized to be a new important and indispensable structural element beneficial to the activity of AST mimics. PMID:25751662

Xie, Yong; Zhang, Li; Zhang, Chuanliang; Wu, Xiaoqing; Deng, Xile; Yang, Xinling; Tobe, Stephen S

2015-03-25

337

Volume 8 (2007), Issue 3, Article 65, 5 pp. ON INEQUALITIES FOR HYPERGEOMETRIC ANALOGUES OF THE  

E-print Network

OF THE ARITHMETIC-GEOMETRIC MEAN ROGER W. BARNARD AND KENDALL C. RICHARDS TEXAS TECH UNIVERSITY LUBBOCK, TEXAS 79409 present sharp inequalities relating hypergeometric analogues of the arithmetic-geometric mean discussed for the arithmetic-geometric mean established in [10]. Key words and phrases: Arithmetic-geometric mean

Barnard, Roger

338

Synthesis of carbocyclic analogues of 4'-ethynyl- and 4'-cyano-d4T.  

PubMed

Synthesis of carbocyclic analogues of 4'-ethynyl and cyano-d4T (4 and 5) was investigated. The ethynyl or cyano group was constructed by conversion of the ester function of key intermediate 13. The carbocyclic unit 12 was prepared from readily available beta-keto ester 6. PMID:17150468

Kumamoto, Hiroki; Kato, Keisuke; Haraguchi, Kazuhiro; Tanaka, Hiromichi; Nitanda, Takao; Baba, Masanori; Dutschman, Ginger E; Cheng, Yung-Chi

2004-01-01

339

Biomimetic N-Terminal Alkylation of Peptoid Analogues of Surfactant Protein C  

E-print Network

Biomimetic N-Terminal Alkylation of Peptoid Analogues of Surfactant Protein C Nathan J. Brown Surfactant protein C (SP-C) is a hydrophobic lipopeptide that is critical for lung function, in part because it physically catalyzes the formation of surface-associated surfactant reservoirs. Many of SP-C's key

Barron, Annelise E.

340

New Insight into the Transcarbamylase Family: The Structure of Putrescine Transcarbamylase, a Key Catalyst for Fermentative Utilization of Agmatine  

PubMed Central

Transcarbamylases reversibly transfer a carbamyl group from carbamylphosphate (CP) to an amine. Although aspartate transcarbamylase and ornithine transcarbamylase (OTC) are well characterized, little was known about putrescine transcarbamylase (PTC), the enzyme that generates CP for ATP production in the fermentative catabolism of agmatine. We demonstrate that PTC (from Enterococcus faecalis), in addition to using putrescine, can utilize L-ornithine as a poor substrate. Crystal structures at 2.5 Å and 2.0 Å resolutions of PTC bound to its respective bisubstrate analog inhibitors for putrescine and ornithine use, N-(phosphonoacetyl)-putrescine and ?-N-(phosphonoacetyl)-L-ornithine, shed light on PTC preference for putrescine. Except for a highly prominent C-terminal helix that projects away and embraces an adjacent subunit, PTC closely resembles OTCs, suggesting recent divergence of the two enzymes. Since differences between the respective 230 and SMG loops of PTC and OTC appeared to account for the differential preference of these enzymes for putrescine and ornithine, we engineered the 230-loop of PTC to make it to resemble the SMG loop of OTCs, increasing the activity with ornithine and greatly decreasing the activity with putrescine. We also examined the role of the C-terminal helix that appears a constant and exclusive PTC trait. The enzyme lacking this helix remained active but the PTC trimer stability appeared decreased, since some of the enzyme eluted as monomers from a gel filtration column. In addition, truncated PTC tended to aggregate to hexamers, as shown both chromatographically and by X-ray crystallography. Therefore, the extra C-terminal helix plays a dual role: it stabilizes the PTC trimer and, by shielding helix 1 of an adjacent subunit, it prevents the supratrimeric oligomerizations of obscure significance observed with some OTCs. Guided by the structural data we identify signature traits that permit easy and unambiguous annotation of PTC sequences. PMID:22363663

Polo, Luis Mariano; Gil-Ortiz, Fernando; Cantín, Angel; Rubio, Vicente

2012-01-01

341

A structurally dynamic N-terminal helix is a key functional determinant in staphylococcal complement inhibitor (SCIN) proteins.  

PubMed

Complement is a network of interacting circulatory and cell surface proteins that recognizes, marks, and facilitates clearance of microbial invaders. To evade complement attack, the pathogenic organism Staphylococcus aureus expresses a number of secreted proteins that interfere with activation and regulation of the complement cascade. Staphylococcal complement inhibitors (SCINs) are one important class of these immunomodulators and consist of three active members (SCIN-A/-B/-C). SCINs inhibit a critical enzymatic complex, the alternative pathway C3 convertase, by targeting a functional "hot spot" on the central opsonin of complement, C3b. Although N-terminal truncation mutants of SCINs retain complement inhibitory properties, they are significantly weaker binders of C3b. To provide a structural basis for this observation, we undertook a series of crystallographic and NMR dynamics studies on full-length SCINs. This work reveals that N-terminal SCIN domains are characterized by a conformationally dynamic helical motif. C3b binding and functional experiments further demonstrate that this sequence-divergent N-terminal region of SCINs is both functionally important and context-dependent. Finally, surface plasmon resonance data provide evidence for the formation of inhibitor·enzyme·substrate complexes ((SCIN·C3bBb)·C3). Similar to the (SCIN·C3bBb)(2) pseudodimeric complexes, ((SCIN·C3bBb)·C3) interferes with the interaction of complement receptors and C3b. This activity provides an additional mechanism by which SCIN couples convertase inhibition to direct blocking of phagocytosis. Together, these data suggest that tethering multi-host protein complexes by small modular bacterial inhibitors may be a global strategy of immune evasion used by S. aureus. The work presented here provides detailed structure-activity relationships and improves our understanding of how S. aureus circumvents human innate immunity. PMID:23233676

Garcia, Brandon L; Summers, Brady J; Ramyar, Kasra X; Tzekou, Apostolia; Lin, Zhuoer; Ricklin, Daniel; Lambris, John D; Laity, John H; Geisbrecht, Brian V

2013-01-25

342

Hydrocode modeling of the largest impact crater on Lutetia, a key to the inner structure of the asteroid  

NASA Astrophysics Data System (ADS)

The question whether the asteroid (21)Lutetia is differentiated or not is highly debated since ESA's spacecraft Rosetta flew by the asteroid on the 10th of July 2010. High resolution images from the OSIRIS camera system [1] and mass estimation from RSI experiment [2] lead to an average density of 3400 kg/m3, larger than what is normally expected for an asteroid (see [3] for typical densities). As we know the surface to be very porous (density 2400 kg/m3) for the first kilometers we expect much denser layers below, and some level of differentiation. So far no mineralogical evidence has been found to support or invalidate this hypothesis. The possibility has been investigated by many authors. The study of [4] showed that Lutetia is at the limit of differentiation. From what we know of this asteroid, only minor differences in its initial composition and location in the accretion disk would shift the balance towards a differentiated body or not. [5] investigated this problem by reconstructing the gravity field of Lutetia assuming different possible inner structures (no, partial, and full differentiation) and studied how the resulting gravity pattern on the surface would be compatible with the observed avalanches and other granular flows. They found that most of the visible flows require a gravity field that is more in agreement with a differentiated Lutetia, although this evidence is very tenuous. We tested the inner structure scenarios (Fig.1) proposed by [5] by performing impact simulations using iSALE hydrocode [6, 7, 8]. The same code is used by [9] to investigate the shape of two craters on Lutetia but without considering explicitly the influence of differentiation. We used our model to put some constraints on the density and layering of the first 5 to 10 km surface layer which can be responsible for the crater morphology [10]. We also discussed qualitatively the effects of different interior models on the shape (Fig.2) of the largest crater Massilia (?55 km in diameter, ?5 km in depth) observed on Lutetia. This current study is the continuation of the previously presented work. We compare now all morphological parameters of the craters obtained from our simulations with the real ones derived from the shape model produced by [11]. We look in details at the topographic profiles, diameter and depth, and the slopes distributions in the crater flanks, for several realistic interior models.

Oklay, N.; Vincent, J.-B.; Sierks, H.; Wünnemann, K.; Elbeshausen, D.

2012-09-01

343

Determination of key structure-activity relationships in siRNA delivery with a mixed micelle system.  

PubMed

Short interfering ribonucleic acids (siRNAs) offer a highly specific and selective form of therapy for diseases with a genetic component; however the poor pharmacokinetic properties of the molecule have impeded its development into a therapeutic for use in vivo. Several different approaches have been taken to develop a successful siRNA delivery system but these systems lack the flexibility for easy optimisation. Here, we propose a polymeric nanoparticle (PNP) system consisting of two amphiphilic diblock copolymers which allow for the rapid determination of structure-activity relationships involving gene knockdown and toxicity. The diblock copolymers self-assemble into monodisperse micelles of defined hydrodynamic diameters ranging from 30 to 100 nm dependent on the copolymer ratio. A luciferase-based high throughput assay varying PNP composition, concentration and siRNA concentration allowed the rapid identification of efficient PNP formulations for adherent and suspension cell lines. Optimised PNPs efficiently knocked down a fusion oncogene in hard to transfect human leukaemic cells raising the possibility of targeting malignant cells in a cancer-specific fashion. This approach allows the optimum PNP formulation to be identified for different cell types and conditions. PMID:24140749

Omedes Pujol, Marta; Coleman, Daniel J L; Allen, Christopher D; Heidenreich, Olaf; Fulton, David A

2013-12-28

344

Determination of key structure–activity relationships in siRNA delivery with a mixed micelle system???  

PubMed Central

Short interfering ribonucleic acids (siRNAs) offer a highly specific and selective form of therapy for diseases with a genetic component; however the poor pharmacokinetic properties of the molecule have impeded its development into a therapeutic for use in vivo. Several different approaches have been taken to develop a successful siRNA delivery system but these systems lack the flexibility for easy optimisation. Here, we propose a polymeric nanoparticle (PNP) system consisting of two amphiphilic diblock copolymers which allow for the rapid determination of structure–activity relationships involving gene knockdown and toxicity. The diblock copolymers self-assemble into monodisperse micelles of defined hydrodynamic diameters ranging from 30 to 100 nm dependent on the copolymer ratio. A luciferase-based high throughput assay varying PNP composition, concentration and siRNA concentration allowed the rapid identification of efficient PNP formulations for adherent and suspension cell lines. Optimised PNPs efficiently knocked down a fusion oncogene in hard to transfect human leukaemic cells raising the possibility of targeting malignant cells in a cancer-specific fashion. This approach allows the optimum PNP formulation to be identified for different cell types and conditions. PMID:24140749

Omedes Pujol, Marta; Coleman, Daniel J.L.; Allen, Christopher D.; Heidenreich, Olaf; Fulton, David A.

2013-01-01

345

Microbial community structure stability, a key parameter in monitoring the development of constructed wetland mesocosms during start-up.  

PubMed

Constructed wetlands (CWs) are known to be effective for treating waste streams, and pilot-scale CWs are useful for assessing the impact of pollutants and their remediation. However, little is known with respect to the establishment of these mesocosm systems or the parameters which should be monitored in assessing system equilibration, i.e. when they present stabilised physical and biological patterns. The aim of this study was to evaluate the temporal aspects of CW equilibration as a basis for future studies of system response to amendment. Microbial biomass and hydraulic conductivity values were monitored and microbial community fingerprints were obtained using denaturing gradient gel electrophoresis (DGGE). This study showed that microbial community fingerprinting provides a valuable tool for assessing the time scales of equilibration, as it was the last parameter which stabilised during the equilibration period. Hydraulic conductivity was also an important parameter in determining the time scale for initiation of the equilibration process during the study. For a CW of the dimensions used (173 cm long/106 cm large/30 cm depth), community equilibration times demonstrated on the basis of similar microbial community structures were found to be on the order of 100 days. PMID:22027103

Ramond, Jean-Baptiste; Welz, Pamela J; Cowan, Don A; Burton, Stephanie G

2012-01-01

346

Cup-shaped Intrusions, Morphology and Emplacement Mechanism Investigate Through Analogue Modelling  

NASA Astrophysics Data System (ADS)

We investigate the morphology of large-scale shallow-depth magma intrusions and sub-volcanic complexes with analogue models. Intrusions of analogue magma are done in a granular material that can contain a ductile layer. The model surface is flat to model the formation of plutonic intrusions and it is overlain by a cone when modelling late sub-volcanic complexes. For flat-top models, we obtain cup-shaped intrusions fed by dykes. Cup-shaped intrusions are inverted-cone like bodies. They are different from saucer-shaped intrusions as they possess neither a well developed sill-base, nor an outer rim. However, like saucers, cups are shallow depth intrusions that dome the country rocks. They initiate from an advancing dyke and first develop an inverted-cone like morphology. Then, the central thickness increases and thrusts form at the edge of the domed country rocks. At this stage, the intrusions progressively involve toward a lopolith shape. By using analogue magma of various viscosities we have been able to constrain key relationships: higher intrusion viscosity causes deeper initiation and the deeper they initiate, the larger is the intrusion diameter. A natural example of such intrusion might by the circles of volcanoes like the Azufre-Lastaria (Peru) that might be overlain be a large-scale cup-shaped intrusion. When adding a cone at the surface of the model and, sometimes, a thin ductile layer in the substratum, the morphology of cup-shaped intrusions vary. Note that the ductile layer of our models is not thick enough to induce the gravitational spreading of the cone. Generally, cup-shaped intrusions are asymmetric in cross section and elliptical in plan view. Their formation creates extension structures in the cone (croissant-shaped rift, straight rift or normal fault) and thrusts in some sectors below the cone. Both types of structures are bordered by strike-slip faults. Cups and saucers share many similarities, but differ probably in the fact that saucers are partially sills that are guided by stratigraphic horizons. However, the basic formation mechanisms may be the same and saucers could be regarded as a special form of cup.

Mathieu, L.; van Wyk de Vries, B.

2007-12-01

347

Structure of Rhodococcus equi virulence-associated protein B (VapB) reveals an eight-stranded antiparallel ?-barrel consisting of two Greek-key motifs  

PubMed Central

Members of the virulence-associated protein (Vap) family from the pathogen Rhodococcus equi regulate virulence in an unknown manner. They do not share recognizable sequence homology with any protein of known structure. VapB and VapA are normally associated with isolates from pigs and horses, respectively. To contribute to a molecular understanding of Vap function, the crystal structure of a protease-resistant VapB fragment was determined at 1.4?Å resolution. The structure was solved by SAD phasing employing the anomalous signal of one endogenous S atom and two bound Co ions with low occupancy. VapB is an eight-stranded antiparallel ?-barrel with a single helix. Structural similarity to avidins suggests a potential binding function. Unlike other eight- or ten-stranded ?-barrels found in avidins, bacterial outer membrane proteins, fatty-acid-binding proteins and lysozyme inhibitors, Vaps do not have a next-neighbour arrangement but consist of two Greek-key motifs with strand order 41238567, suggesting an unusual or even unique topology. PMID:25005079

Geerds, Christina; Wohlmann, Jens; Haas, Albert; Niemann, Hartmut H.

2014-01-01

348

Interaction of cis-(6-benzhydrylpiperidin-3-yl)benzylamine analogues with monoamine transporters: structure-activity relationship study of structurally constrained 3,6-disubstituted piperidine analogues of (2,2-diphenylethyl)-[1-(4-fluorobenzyl)piperidin-4-ylmethyl]amine.  

PubMed

To explore structure-activity relationships (SAR) of a novel conformationally constrained lead cis-3,6-disubstituted piperidine derivative derived from (2,2-diphenylethyl)-[1-(4-fluorobenzyl)piperidine-4-ylmethyl]amine (I), a series of compounds was synthesized by derivatizing the exocyclic N-atom at the 3-position of the lead. This study led to the formation of substituted phenyl and heterocyclic derivatives. All novel compounds were tested for their affinity at the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) in the brain by measuring their potency in competing for the binding of [3H]WIN 35 428, [3H]citalopram, and [3H]nisoxetine, respectively. Selected compounds were also evaluated for their activity in inhibiting the uptake of [3H]DA. The SAR results demonstrated that the nature of substitutions on the phenyl ring is important in activity at the DAT with the presence of an electron-withdrawing group having the maximum effect on potency. Replacement of the phenyl ring in the benzyl group by heterocyclic moieties resulted in the development of compounds with moderate activity for the DAT. Two most potent racemic compounds were separated by a diastereoisomeric separation procedure, and differential affinities were observed for the enantiomers. Absolute configuration of the enantiomers was obtained unambiguously by X-ray crystal structural study. One of the enantiomers, compound S,S-(-)-19a, exhibited the highest potency for the DAT (IC50 = 11.3 nM) among all the compounds tested and was as potent as GBR 12909 (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine). However, the compound (-)-19a was more selective than GBR 12909 in binding to the DAT compared with binding to the SERT and NET. The present results establish the newly developed 3,6-disubstituted piperidine derivatives as a novel template for high-affinity inhibitors of DAT. Structurally these molecules are more constrained compared to our earlier flexible piperidine molecules and, thus, should provide more insights about their bioactive conformations. PMID:12747792

Kolhatkar, Rohit B; Ghorai, Sujit K; George, Clifford; Reith, Maarten E A; Dutta, Aloke K

2003-05-22

349

Natural analogue studies as supplements to biomineralization research  

SciTech Connect

Chemical reactions can alter the chemistry and crystal structure of solid objects over archeological or geological times, while preserving external physical shapes. The reactions resulting in these structures offer natural analogues to laboratory experiments in biomineralization and to biologically influenced alteration of nuclear waste packages, and thus, they offer the only available way of validating models that purport waste package behavior over archaeological or geological times. Potential uses of such analogues in the construction and validation of hypothetical mechanisms of microbiological corrosion and biomineralization are reviewed. Evidence from such analogues suggests that biofilms can control materials alteration in ways usually overlooked. The newly hypothesized mechanisms involve control by biofilms of the cation flow near the solid surface and offer plausible mechanisms for the formation of mixed-cation minerals under conditions that would lead to dealloying in abiotic experiments; they also account for the formation of unusual minerals [such as posnjakite, Cu{sub 4}SO{sub 4}(OH){sub 6{center_dot}}H{sub 2}O] and mineral morphologies unusual in corrosion [malachite, Cu{sub 2}CO{sub 3}(OH){sub 2}, rarely forms botryoidally under corrosion conditions and its occasional presence on archaeological objects that appear to have undergone microbiological corrosion may be related to biofilm phenomena].

McNeil, M.B. [Nuclear Regulatory Commission, Washington, DC (United States)

1995-09-01

350

Analogue Transformations in Physics and their Application to Acoustics  

NASA Astrophysics Data System (ADS)

Transformation optics has shaped up a revolutionary electromagnetic design paradigm, enabling scientists to build astonishing devices such as invisibility cloaks. Unfortunately, the application of transformation techniques to other branches of physics is often constrained by the structure of the field equations. We develop here a complete transformation method using the idea of analogue spacetimes. The method is general and could be considered as a new paradigm for controlling waves in different branches of physics, from acoustics in quantum fluids to graphene electronics. As an application, we derive an ``analogue transformation acoustics'' formalism that naturally allows the use of transformations mixing space and time or involving moving fluids, both of which were impossible with the standard approach. To demonstrate the power of our method, we give explicit designs of a dynamic compressor, a spacetime cloak for acoustic waves and a carpet cloak for a moving aircraft.

García-Meca, C.; Carloni, S.; Barceló, C.; Jannes, G.; Sánchez-Dehesa, J.; Martínez, A.

2013-06-01

351

Analogue Transformations in Physics and their Application to Acoustics  

PubMed Central

Transformation optics has shaped up a revolutionary electromagnetic design paradigm, enabling scientists to build astonishing devices such as invisibility cloaks. Unfortunately, the application of transformation techniques to other branches of physics is often constrained by the structure of the field equations. We develop here a complete transformation method using the idea of analogue spacetimes. The method is general and could be considered as a new paradigm for controlling waves in different branches of physics, from acoustics in quantum fluids to graphene electronics. As an application, we derive an “analogue transformation acoustics” formalism that naturally allows the use of transformations mixing space and time or involving moving fluids, both of which were impossible with the standard approach. To demonstrate the power of our method, we give explicit designs of a dynamic compressor, a spacetime cloak for acoustic waves and a carpet cloak for a moving aircraft. PMID:23774575

García-Meca, C.; Carloni, S.; Barceló, C.; Jannes, G.; Sánchez-Dehesa, J.; Martínez, A.

2013-01-01

352

Analogue transformations in physics and their application to acoustics.  

PubMed

Transformation optics has shaped up a revolutionary electromagnetic design paradigm, enabling scientists to build astonishing devices such as invisibility cloaks. Unfortunately, the application of transformation techniques to other branches of physics is often constrained by the structure of the field equations. We develop here a complete transformation method using the idea of analogue spacetimes. The method is general and could be considered as a new paradigm for controlling waves in different branches of physics, from acoustics in quantum fluids to graphene electronics. As an application, we derive an "analogue transformation acoustics" formalism that naturally allows the use of transformations mixing space and time or involving moving fluids, both of which were impossible with the standard approach. To demonstrate the power of our method, we give explicit designs of a dynamic compressor, a spacetime cloak for acoustic waves and a carpet cloak for a moving aircraft. PMID:23774575

García-Meca, C; Carloni, S; Barceló, C; Jannes, G; Sánchez-Dehesa, J; Martínez, A

2013-01-01

353

Plant Volatile Analogues Strengthen Attractiveness to Insect  

PubMed Central

Green leaf bug Apolygus lucorum (Meyer-Dür) is one of the major pests in agriculture. Management of A. lucorum was largely achieved by using pesticides. However, the increasing population of A. lucorum since growing Bt cotton widely and the increased awareness of ecoenvironment and agricultural product safety makes their population-control very challenging. Therefore this study was conducted to explore a novel ecological approach, synthetic plant volatile analogues, to manage the pest. Here, plant volatile analogues were first designed and synthesized by combining the bioactive components of ?-ionone and benzaldehyde. The stabilities of ?-ionone, benzaldehyde and analogue 3 g were tested. The electroantennogram (EAG) responses of A. lucorum adult antennae to the analogues were recorded. And the behavior assay and filed experiment were also conducted. In this study, thirteen analogues were acquired. The analogue 3 g was demonstrated to be more stable than ?-ionone and benzaldehyde in the environment. Many of the analogues elicited EAG responses, and the EAG response values to 3 g remained unchanged during seven-day period. 3 g was also demonstrated to be attractive to A. lucorum adults in the laboratory behavior experiment and in the field. Its attractiveness persisted longer than ?-ionone and benzaldehyde. This indicated that 3 g can strengthen attractiveness to insect and has potential as an attractant. Our results suggest that synthetic plant volatile analogues can strengthen attractiveness to insect. This is the first published study about synthetic plant volatile analogues that have the potential to be used in pest control. Our results will support a new ecological approach to pest control and it will be helpful to ecoenvironment and agricultural product safety. PMID:24911460

Sun, Yufeng; Yu, Hao; Zhou, Jing-Jiang; Pickett, John A.; Wu, Kongming

2014-01-01

354

Plant volatile analogues strengthen attractiveness to insect.  

PubMed

Green leaf bug Apolygus lucorum (Meyer-Dür) is one of the major pests in agriculture. Management of A. lucorum was largely achieved by using pesticides. However, the increasing population of A. lucorum since growing Bt cotton widely and the increased awareness of ecoenvironment and agricultural product safety makes their population-control very challenging. Therefore this study was conducted to explore a novel ecological approach, synthetic plant volatile analogues, to manage the pest. Here, plant volatile analogues were first designed and synthesized by combining the bioactive components of ?-ionone and benzaldehyde. The stabilities of ?-ionone, benzaldehyde and analogue 3 g were tested. The electroantennogram (EAG) responses of A. lucorum adult antennae to the analogues were recorded. And the behavior assay and filed experiment were also conducted. In this study, thirteen analogues were acquired. The analogue 3 g was demonstrated to be more stable than ?-ionone and benzaldehyde in the environment. Many of the analogues elicited EAG responses, and the EAG response values to 3 g remained unchanged during seven-day period. 3 g was also demonstrated to be attractive to A. lucorum adults in the laboratory behavior experiment and in the field. Its attractiveness persisted longer than ?-ionone and benzaldehyde. This indicated that 3 g can strengthen attractiveness to insect and has potential as an attractant. Our results suggest that synthetic plant volatile analogues can strengthen attractiveness to insect. This is the first published study about synthetic plant volatile analogues that have the potential to be used in pest control. Our results will support a new ecological approach to pest control and it will be helpful to ecoenvironment and agricultural product safety. PMID:24911460

Sun, Yufeng; Yu, Hao; Zhou, Jing-Jiang; Pickett, John A; Wu, Kongming

2014-01-01

355

Conserved structure and varied expression reveal key roles of phosphoglucan phosphatase gene starch excess 4 in barley.  

PubMed

As one of the phosphoglucan phosphatases, starch excess 4 (SEX4) encoded by SEX4 gene has recently been intensively studied because of its vital role in the degradation of leaf starch. In this study, we isolated and chromosomally mapped barley SEX4, characterized its gene and protein structure, predicted the cis-elements of its promoter, and analysed its expression based on real-time quantitative PCR and publically available microarray data. The full length of barely SEX4 (HvSEX4) was 4,598 bp and it was mapped on the long arm of chromosome 4H (4HL). This gene contained 14 exons and 13 introns in all but two of the species analysed, Arabidopsis (13 exons and 12 introns) and Oryza brachyantha (12 exons and 11 introns). An exon-intron junction composed of intron 4 to intron 7 and exon 5 to exon 8 was highly conserved among the analysed species. SEX4 is characterized with conserved functional domains (dual specificity phosphatase domain and carbohydrate-binding module 48) and varied chloroplast transit peptide and C-terminal. Expression analyses indicated that: (1) SEX4 was mainly expressed in anthers of barley, young leaf and anthers of rice, and leaf of Arabidopsis; (2) it exhibited a diurnal pattern in barley, rice and Arabidopsis; (3) significant difference in the expression of SEX4 was not detected for either barley or rice under any of the investigated stresses; and (4) it was significantly down-regulated at middle stage and up-regulated at late stage under cold treatment, down-regulated at early stage under heat treatment, and up-regulated at late stage under salt treatment in Arabidopsis. The strong relationships detected in the current study between SEX4 and glucan, water dikinases (GWD) or phosphoglucan, water dikinases (PWD) were discussed. Collectively, our results provide insights into genetic manipulation of SEX4, especially in monocotyledon and uncovering the possible roles of SEX4 in plant development. PMID:25100144

Ma, Jian; Jiang, Qian-Tao; Wei, Long; Yang, Qiang; Zhang, Xiao-Wei; Peng, Yuan-Ying; Chen, Guo-Yue; Wei, Yu-Ming; Liu, Chunji; Zheng, You-Liang

2014-12-01

356

Characterization of photophysical and base-mimicking properties of a novel fluorescent adenine analogue in DNA  

PubMed Central

To increase the diversity of fluorescent base analogues with improved properties, we here present the straightforward click-chemistry-based synthesis of a novel fluorescent adenine-analogue triazole adenine (AT) and its photophysical characterization inside DNA. AT shows promising properties compared to the widely used adenine analogue 2-aminopurine. Quantum yields reach >20% and >5% in single- and double-stranded DNA, respectively, and show dependence on neighbouring bases. Moreover, AT shows only a minor destabilization of DNA duplexes, comparable to 2-aminopurine, and circular dichroism investigations suggest that AT only causes minimal structural perturbations to normal B-DNA. Furthermore, we find that AT shows favourable base-pairing properties with thymine and more surprisingly also with normal adenine. In conclusion, AT shows strong potential as a new fluorescent adenine analogue for monitoring changes within its microenvironment in DNA. PMID:21278417

Dierckx, Anke; Dinér, Peter; El-Sagheer, Afaf H.; Kumar, Joshi Dhruval; Brown, Tom; Grøtli, Morten; Wilhelmsson, L. Marcus

2011-01-01

357

Molecular Dynamics of Sialic Acid Analogues and their Interaction with Influenza Hemagglutinin  

PubMed Central

Synthetic sialic acid analogues with multiple modifications at different positions(C-1/C-2/C-4/C-8/C-9) are investigated by molecular mechanics and molecular dynamics to determine their conformational preferences and structural stability to interact with their natural receptors. Sialic acids with multiple modifications are soaked in a periodic box of water as solvent. Molecular mechanics and a 2 nanosecond molecular dynamics are done using amber force fields with 30 picosecond equilibrium. Direct and water mediated hydrogen bonds existing in the sialic acid analogues, aiding for their structural stabilization are identified in this study. The accessible conformations of side chain linkages of sialic acid analogues holding multiple substituents are determined from molecular dynamics trajectory at every 1ps interval. Transitions between different minimum energy regions in conformational maps are also noticed in C-1, C-2, C-4, C-8 and C-9 substituents. Docking studies were done to find the binding mode of the sialic acid analogues with Influenza hemagglutinin. This finding provides stereo chemical explanation and conformational preference of sialic acid analogues which may be crucial for the design of sialic acid analogues as inhibitors for different sialic acid specific pathogenic proteins such as influenza toxins and neuraminidases. PMID:21218055

Blessia, T. Femlin; Rapheal, V. S.; Sharmila, D. J. S.

2010-01-01

358

Farnesyl diphosphate analogues with aryl moieties are efficient alternate substrates for protein farnesyltransferase.  

PubMed

Farnesylation is an important post-translational modification essential for the proper localization and function of many proteins. Transfer of the farnesyl group from farnesyl diphosphate (FPP) to proteins is catalyzed by protein farnesyltransferase (FTase). We employed a library of FPP analogues with a range of aryl groups substituting for individual isoprene moieties to examine some of the structural and electronic properties of the transfer of an analogue to the peptide catalyzed by FTase. Analysis of steady-state kinetics for modification of peptide substrates revealed that the multiple-turnover activity depends on the analogue structure. Analogues in which the first isoprene is replaced with a benzyl group and an analogue in which each isoprene is replaced with an aryl group are good substrates. In sharp contrast with the steady-state reaction, the single-turnover rate constant for dansyl-GCVLS alkylation was found to be the same for all analogues, despite the increased chemical reactivity of the benzyl analogues and the increased steric bulk of other analogues. However, the single-turnover rate constant for alkylation does depend on the Ca(1)a(2)X peptide sequence. These results suggest that the isoprenoid transition-state conformation is preferred over the inactive E·FPP·Ca(1)a(2)X ternary complex conformation. Furthermore, these data suggest that the farnesyl binding site in the exit groove may be significantly more selective for the farnesyl diphosphate substrate than the active site binding pocket and therefore might be a useful site for the design of novel inhibitors. PMID:22989235

Subramanian, Thangaiah; Pais, June E; Liu, Suxia; Troutman, Jerry M; Suzuki, Yuta; Leela Subramanian, Karunai; Fierke, Carol A; Andres, Douglas A; Spielmann, H Peter

2012-10-16

359

Structure-activity relationship studies of highly selective inhibitors of the dopamine transporter: N-benzylpiperidine analogues of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine.  

PubMed

A series of 4-[2-[bis(4-fluorophenyl)methoxy]ethyl-1-benzylpiperidines were examined for their ability to bind to the dopamine transporter (DAT), the serotonin transporter (SERT), and the norepinephrine transporter (NET). Binding results indicated that the presence of an electron-withdrawing group in the C(4)-position of the N-benzyl group is beneficial for binding to the DAT. Several analogues have been identified with high affinity for the DAT, up to 500-fold selectivity over the SERT and about 170-fold selectivity over the NET in binding and uptake inhibition assays. PMID:12672246

Greiner, Elisabeth; Prisinzano, Thomas; Johnson, Edward M; Dersch, Christina M; Marcus, Jamila; Partilla, John S; Rothman, Richard B; Jacobson, Arthur E; Rice, Kenner C

2003-04-10

360

The Spectral Properties and Photosensitivities of Analogue Photopigments Regenerated with 10- and 14-Substituted Retinal Analogues  

Microsoft Academic Search

Analogues of 11-cis- and 9-cis-retinal with substitutions at positions 10 and 14 were used to regenerate analogue photopigments with two opsins: that of the transmuted (cone-like) 521-pigment of Gekko gekko and that of the rhodopsin of Porichthys notatus. The spectral absorbances and photosensitivities of the regenerated photopigments were determined and compared, first, between the two systems of analogue photopigments, and

F. Crescitelli; R. S. H. Liu

1988-01-01

361

Space analogue studies in Antarctica  

NASA Astrophysics Data System (ADS)

Medical research has been carried out on the Australian National Antarctic Research Expeditions (ANARE) for 50 years. As an extension of this program collaborative Australian/United States research on immunology, microbiology, psychology and remote medicine has produced important data and insight on how humans adapt to the stress of extreme isolation, confinement and the harsh environment of Antarctica. An outstanding analogue for the isolation and confinement of space missions (especially planetary outposts), ANARE has been used as an international research platform by Australia and the United States since 1993. Collaborative research has demonstrated a lowered responsiveness of the immune system under the isolation and confinement of Antarctic winter-over; a reduction of almost 50% in T cell proliferation to mltogen phytohaemogglutinin, as well as changes in latent herpesvirus states and the expansion of the polyclonal latent Epstein-Barr virus infected B cell populations. Although no clinically significant disease has been found to result from these immune changes, research is currently assessing the effects of psychological factors on the immune system. This and associated research performed to date and its relevance to both organisations is discussed, and comment made on possible extensions to the program in both medical and other fields.

Lugg, D.; Shepanek, M.

1999-09-01

362

Space analogue studies in Antarctica  

NASA Technical Reports Server (NTRS)

Medical research has been carried out on the Australian National Antarctic Research Expeditions (ANARE) for 50 years. As an extension of this program collaborative Australian/United States research on immunology, microbiology, psychology and remote medicine has produced important data and insight on how humans adapt to the stress of extreme isolation, confinement and the harsh environment of Antarctica. An outstanding analogue for the isolation and confinement of space missions (especially planetary outposts), ANARE has been used as an international research platform by Australia and the United States since 1993. Collaborative research has demonstrated a lowered responsiveness of the immune system under the isolation and confinement of Antarctic winter-over; a reduction of almost 50% in T cell proliferation to mitogen phytohaemogglutinin, as well as changes in latent herpesvirus states and the expansion of the polyclonal latent Epstein-Barr virus infected B cell populations. Although no clinically significant disease has been found to result from these immune changes, research is currently assessing the effects of psychological factors on the immune system. This and associated research performed to date and its relevance to both organisations is discussed, and comment made on possible extensions to the program in both medical and other fields.

Lugg, D.; Shepanek, M.

1999-01-01

363

Arctic Mars Analogue Svalbard Expedition (AMASE) 2009  

NASA Astrophysics Data System (ADS)

The Arctic Mars Analogue Svalbard Expeditions (AMASE) 2009 was the latest of a series of expeditions that are NASA ASTEP and ESA funded and have as among their primary goals sample acquisition, collection and caching on rover platforms.

Steele, A.; Amundsen, H. E. F.; Conrad, P.; Benning, L.; Amase 2009 Team

2010-03-01

364

Anisotropic charged analogue of Heintzmann's solution  

NASA Astrophysics Data System (ADS)

We present an anisotropic charged analogue of Heintzmann's (Z. Phys. 228:489, 1969) solution of the general relativistic field equations in curvature coordinates by using simple form of electric intensity E and pressure anisotropy factor ? that involve charge parameter K and anisotropy parameter ? respectively. Our solution is well behaved in all respects for all values of X lying in the range 0structure of compact stars.

Pradhan, N.; Pant, Neeraj

2014-12-01

365

Anisotropic charged analogue of Heintzmann's solution  

NASA Astrophysics Data System (ADS)

We present an anisotropic charged analogue of Heintzmann's (Z. Phys. 228:489, 1969) solution of the general relativistic field equations in curvature coordinates by using simple form of electric intensity E and pressure anisotropy factor ? that involve charge parameter K and anisotropy parameter ? respectively. Our solution is well behaved in all respects for all values of X lying in the range 0< X?1.1, ? lying in the range 0? ??6.2, K lying in the range 0< K?9.7 and Schwarzschild compactness parameter " u" lying in the range 0< u?0.391. Since our solution is well behaved for a wide ranges of the parameters, we can model many different types of ultra-cold compact stars like quark stars and neutron stars. We present some models of super dense quark star and neutron stars corresponding to X=0.1, ?=1 and K=3. By assuming surface density of quark star, ? b =4.6888×1014 g cm-3 the mass and radius are 1.271 M ?, 10.09 km respectively. For ? b =2.7×1014 g cm-3 the mass and radius of neutron star are 1.675 M ?, 13.297 km respectively. The well behaved class of relativistic stellar models obtained in this work might have astrophysical significance in the study of more realistic internal structure of compact stars.

Pradhan, N.; Pant, Neeraj

2015-03-01

366

Conformational freedom in tight binding enzymatic transition-state analogues.  

PubMed

Transition-state analogues of bacterial 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidases (MTANs) disrupt quorum-sensing pathways in Escherichia coli and Vibrio cholerae, demonstrating the potential to limit pathogenicity without placing bacteria under intense selective pressure that leads to antibiotic resistance. Despite the similarity of the crystal structures of E. coli MTAN (EcMTAN) and V. cholerae MTAN (VcMTAN) bound to DADMe-Immucillin-A transition-state (TS) analogues, EcMTAN demonstrates femtomolar affinity for BuT-DADMe-Immucillin-A (BDIA) whereas VcMTAN possesses only picomolar affinity. Protein dynamic interactions are therefore implicated in this inhibitor affinity difference. We conducted molecular dynamics simulations of both EcMTAN and VcMTAN in complex with BDIA to explore differences in protein dynamic architecture. Simulations revealed that electrostatic and hydrophobic interactions with BDIA are similar for both enzymes and thus unlikely to account for the difference in inhibitor affinity. The EcMTAN-BDIA complex reveals a greater flexibility and conformational freedom of catalytically important atoms. We propose that conserved motions related to the EcMTAN transition state correlate with the increased affinity of BDIA for EcMTAN. Transition-state analogues permitting protein motion related to formation of the transition state are better mimics of the enzymatic transition state and can bind more tightly than those immobilizing catalytic site dynamics. PMID:23895500

Motley, Matthew W; Schramm, Vern L; Schwartz, Steven D

2013-08-22

367

Noble gas encapsulation: clathrate hydrates and their HF doped analogues.  

PubMed

The significance of clathrate hydrates lies in their ability to encapsulate a vast range of inert gases. Although the natural abundance of a few noble gases (Kr and Xe) is poor their hydrates are generally abundant. It has already been reported that HF doping enhances the stability of hydrogen hydrates and methane hydrates, which prompted us to perform a model study on helium, neon and argon hydrates with their HF doped analogues. For this purpose 5(12), 5(12)6(8) and their HF doped analogues are taken as the model clathrate hydrates, which are among the building blocks of sI, sII and sH types of clathrate hydrate crystals. We use the dispersion corrected and gradient corrected hybrid density functional theory for the calculation of thermodynamic parameters as well as conceptual density functional theory based reactivity descriptors. The method of the ab initio molecular dynamics (AIMD) simulation is used through atom centered density matrix propagation (ADMP) techniques to envisage the structural behaviour of different noble gas hydrates on a 500 fs timescale. Electron density analysis is carried out to understand the nature of Ng-OH2, Ng-FH and Ng-Ng interactions. The current results noticeably demonstrate that the noble gas (He, Ne, and Ar) encapsulation ability of 5(12), 5(12)6(8) and their HF doped analogues is thermodynamically favourable. PMID:25047071

Mondal, Sukanta; Chattaraj, Pratim Kumar

2014-09-01

368

Synthesis and characterization of mitoQ and idebenone analogues as mediators of oxygen consumption in mitochondria  

PubMed Central

Analogues of mitoQ and idebenone were synthesized to define the structural elements that support oxygen consumption in the mitochondrial respiratory chain. Eight analogues were prepared and fully characterized, then evaluated for their ability to support oxygen consumption in the mitochondrial respiratory chain. While oxygen consumption was strongly inhibited by mitoQ analogues 2–4 in a chain length-dependent manner, modification of idebenone by replacement of the quinone methoxy groups by methyl groups (analogues 6 – 8) reduced, but did not eliminate, oxygen consumption. Idebenone analogues 6 – 8 also displayed significant cytoprotective properties toward cultured mammalian cells in which glutathione had been depleted by treatment with diethyl maleate. PMID:20691600

Duveau, Damien Y.; Arce, Pablo M.; Schoenfeld, Robert A.; Raghav, Nidhi; Cortopassi, Gino A.; Hecht, Sidney M.

2013-01-01

369

Synthesis and protein kinase inhibitory activity of balanol analogues with modified benzophenone subunits.  

PubMed

A series of analogues of the protein kinase C (PKC) inhibitory natural product balanol which bear modified benzophenone subunits are described. The analogues were designed with the goal of uncovering structure-activity features that could be used in the development of PKC inhibitors with a reduced polar character compared to balanol itself. The results of these studies suggest that most of the benzophenone features found in the natural product are important for obtaining potent PKC inhibitory compounds. However, several modifications were found to lead to selective inhibitors of the related enzyme protein kinase A (PKA), and several specific modifications to the polar structural elements of the benzophenone were found to provide potent PKC inhibitors. In particular, it was found that replacement of the benzophenone carboxylate with bioisosteric equivalents could lead to potent analogues. Further, a tolerance for lipophilic substituents on the terminal benzophenone ring was uncovered. These results are discussed in light of recently available structural information for PKA. PMID:12036372

Lampe, John W; Biggers, Christopher K; Defauw, Jean M; Foglesong, Robert J; Hall, Steven E; Heerding, Julia M; Hollinshead, Sean P; Hu, Hong; Hughes, Philip F; Jagdmann, G Erik; Johnson, Mary George; Lai, Yen-Shi; Lowden, Christopher T; Lynch, Michael P; Mendoza, José S; Murphy, Marcia M; Wilson, Joseph W; Ballas, Lawrence M; Carter, Kiyomi; Darges, James W; Davis, Jefferson E; Hubbard, Frederick R; Stamper, Mark L

2002-06-01

370

Crystal structure of the ?-hydroxymuconic semialdehyde dehydrogenase from Pseudomonas sp. strainWBC-3, a key enzyme involved in para-Nitrophenol degradation  

PubMed Central

Background para-Nitrophenol (PNP) is a highly toxic compound with threats to mammalian health. The pnpE-encoded ?-hydroxymuconic semialdehyde dehydrogenase catalyzes the reduction of ?-hydroxymuconic semialdehyde to maleylacetate in Pseudomonas sp. strain WBC-3, playing a key role in the catabolism of PNP to Krebs cycle intermediates. However, the catalyzing mechanism by PnpE has not been well understood. Results Here we report the crystal structures of the apo and NAD bound PnpE. In the PnpE-NAD complex structure, NAD is situated in a cleft of PnpE. The cofactor binding site is composed of two pockets. The adenosine and the first ribose group of NAD bind in one pocket and the nicotinamide ring in the other. Conclusions Six amino acids have interactions with the cofactor. They are C281, E247, Q210, W148, I146 and K172. Highly conserved residues C281 and E247 were identified to be critical for its catalytic activity. In addition, flexible docking studies of the enzyme-substrate system were performed to predict the interactions between PnpE and its substrate ?-hydroxymuconic semialdehyde. Amino acids that interact extensively with the substrate and stabilize the substrate in an orientation suitable for enzyme catalysis were identified. The importance of these residues for catalytic activity was confirmed by the relevant site-directed mutagenesis and their biochemical characterization. PMID:24252642

2013-01-01

371

On Compression of Cryptographic Keys  

E-print Network

Any secured system can be modeled as a capability-based access control system in which each user is given a set of secret keys of the resources he is granted access to. In some large systems with resource-constrained devices, such as sensor networks and RFID systems, the design is sensitive to memory or key storage cost. With a goal to minimize the maximum users' key storage, key compression based on key linking, that is, deriving one key from another without compromising security, is studied. A lower bound on key storage needed for a general access structure with key derivation is derived. This bound demonstrates the theoretic limit of any systems which do not trade off security and can be treated as a negative result to provide ground for designs with security tradeoff. A concrete, provably secure key linking scheme based on pseudorandom functions is given. Using the key linking framework, a number of key pre-distribution schemes in the literature are analyzed.

Chan, Aldar C-F

2007-01-01

372

Protonation states of the key active site residues and structural dynamics of glmS riboswitch as reveled by molecular dynamics  

PubMed Central

The glmS catalytic riboswitch is part of the 5'-untranslated region of mRNAs encoding glucosamine-6-phosphate (GlcN6P) synthetase (glmS) in numerous Gram-positive bacteria. Binding of the cofactor GlcN6P induces site-specific self-cleavage of the RNA. However, detailed reaction mechanism as well as protonation state of glmS reactive form remains still elusive. To probe the dominant protonation states of key active site residues, we carried out explicit solvent molecular dynamic simulations involving various protonation states of three crucial active site moieties observed in the available crystal structures: (i) guanine G40 (following the T. tengcongensis numbering), (ii) the GlcN6P amino/ammonium group, and (iii) the GlcN6P phosphate moiety. We found that a deprotonated G40? seems incompatible with the observed glmS active site architecture. Our data suggest that the canonical form of G40 plays a structural role by stabilizing an in-line attack conformation of the cleavage site A-1(2'-OH) nucleophile, rather than a more direct chemical role. In addition, we observe weakened cofactor binding upon protonation of the GlcN6P phosphate moiety, which explains the experimentally observed increase of Km with decreasing pH. Finally, we discuss a possible role of cofactor binding and its interaction with the G65 and G1 purines in structural stabilization of the A-1(2'-OH) in-line attack conformation. Based on the identified dominant protonation state of the reaction precursor, we propose a hypothesis of self-cleavage mechanism, in which A-1(2'-OH) is activated as nucleophile by the G1(pro-Rp) non-bridging oxygen of the scissile phosphate, whereas the ammonium group of GlcN6P acts as the general acid protonating the G1(O5') leaving group. PMID:20536206

Banáš, Pavel; Walter, Nils G.

2010-01-01

373

Key-Insulated Public Key Cryptosystems  

Microsoft Academic Search

Cryptographic computations (decryption, signature generation, etc.) are often performed on a relatively insecure device (e.g., a mobile device or an Internet-connected host) which cannot be trusted to maintain secrecy of the pri- vate key. We propose and investigate the notion of key-insulated security whose goal is to minimize the damage caused by secret-key exposures. In our model, the secret key(s)

Yevgeniy Dodis; Jonathan Katz; Shouhuai Xu; Moti Yung

2002-01-01

374

Enzymatic synthesis of RNAs capped with nucleotide analogues reveals the molecular basis for substrate selectivity of RNA capping enzyme: impacts on RNA metabolism.  

PubMed

RNA cap binding proteins have evolved to specifically bind to the N7-methyl guanosine cap structure found at the 5' ends of eukaryotic mRNAs. The specificity of RNA capping enzymes towards GTP for the synthesis of this structure is therefore crucial for mRNA metabolism. The fact that ribavirin triphosphate was described as a substrate of a viral RNA capping enzyme, raised the possibility that RNAs capped with nucleotide analogues could be generated in cellulo. Owing to the fact that this prospect potentially has wide pharmacological implications, we decided to investigate whether the active site of the model Paramecium bursaria Chlorella virus-1 RNA capping enzyme was flexible enough to accommodate various purine analogues. Using this approach, we identified several key structural determinants at each step of the RNA capping reaction and generated RNAs harboring various different cap analogues. Moreover, we monitored the binding affinity of these novel capped RNAs to the eIF4E protein and evaluated their translational properties in cellulo. Overall, this study establishes a molecular rationale for the specific selection of GTP over other NTPs by RNA capping enzyme It also demonstrates that RNAs can be enzymatically capped with certain purine nucleotide analogs, and it also describes the impacts of modified RNA caps on specific steps involved in mRNA metabolism. For instance, our results indicate that the N7-methyl group of the classical N7-methyl guanosine cap is not always indispensable for binding to eIF4E and subsequently for translation when compensatory modifications are present on the capped residue. Overall, these findings have important implications for our understanding of the molecular determinants involved in both RNA capping and RNA metabolism. PMID:24086504

Issur, Moheshwarnath; Bougie, Isabelle; Despins, Simon; Bisaillon, Martin

2013-01-01

375

Enzymatic Synthesis of RNAs Capped with Nucleotide Analogues Reveals the Molecular Basis for Substrate Selectivity of RNA Capping Enzyme: Impacts on RNA Metabolism  

PubMed Central

RNA cap binding proteins have evolved to specifically bind to the N7-methyl guanosine cap structure found at the 5’ ends of eukaryotic mRNAs. The specificity of RNA capping enzymes towards GTP for the synthesis of this structure is therefore crucial for mRNA metabolism. The fact that ribavirin triphosphate was described as a substrate of a viral RNA capping enzyme, raised the possibility that RNAs capped with nucleotide analogues could be generated in cellulo. Owing to the fact that this prospect potentially has wide pharmacological implications, we decided to investigate whether the active site of the model Parameciumbursaria Chlorella virus-1 RNA capping enzyme was flexible enough to accommodate various purine analogues. Using this approach, we identified several key structural determinants at each step of the RNA capping reaction and generated RNAs harboring various different cap analogues. Moreover, we monitored the binding affinity of these novel capped RNAs to the eIF4E protein and evaluated their translational properties in cellulo. Overall, this study establishes a molecular rationale for the specific selection of GTP over other NTPs by RNA capping enzyme It also demonstrates that RNAs can be enzymatically capped with certain purine nucleotide analogs, and it also describes the impacts of modified RNA caps on specific steps involved in mRNA metabolism. For instance, our results indicate that the N7-methyl group of the classical N7-methyl guanosine cap is not always indispensable for binding to eIF4E and subsequently for translation when compensatory modifications are present on the capped residue. Overall, these findings have important implications for our understanding of the molecular determinants involved in both RNA capping and RNA metabolism. PMID:24086504

Issur, Moheshwarnath; Bougie, Isabelle; Despins, Simon; Bisaillon, Martin

2013-01-01

376

Discovery of cytotoxic dolastatin 10 analogues with N-terminal modifications.  

PubMed

Auristatins, synthetic analogues of the antineoplastic natural product Dolastatin 10, are ultrapotent cytotoxic microtubule inhibitors that are clinically used as payloads in antibody-drug conjugates (ADCs). The design and synthesis of several new auristatin analogues with N-terminal modifications that include amino acids with ?,?-disubstituted carbon atoms are described, including the discovery of our lead auristatin, PF-06380101. This modification of the peptide structure is unprecedented and led to analogues with excellent potencies in tumor cell proliferation assays and differential ADME properties when compared to other synthetic auristatin analogues that are used in the preparation of ADCs. In addition, auristatin cocrystal structures with tubulin are being presented that allow for the detailed examination of their binding modes. A surprising finding is that all analyzed analogues have a cis-configuration at the Val-Dil amide bond in their functionally relevant tubulin bound state, whereas in solution this bond is exclusively in the trans-configuration. This remarkable observation shines light onto the preferred binding mode of auristatins and serves as a valuable tool for structure-based drug design. PMID:25431858

Maderna, Andreas; Doroski, Matthew; Subramanyam, Chakrapani; Porte, Alexander; Leverett, Carolyn A; Vetelino, Beth C; Chen, Zecheng; Risley, Hud; Parris, Kevin; Pandit, Jayvardhan; Varghese, Alison H; Shanker, Suman; Song, Cynthia; Sukuru, Sai Chetan K; Farley, Kathleen A; Wagenaar, Melissa M; Shapiro, Michael J; Musto, Sylvia; Lam, My-Hanh; Loganzo, Frank; O'Donnell, Christopher J

2014-12-26

377

Himbacine-derived thrombin receptor antagonists: c7-spirocyclic analogues of vorapaxar.  

PubMed

We have synthesized several C7-spirocyclic analogues of vorapaxar and evaluated their in vitro activities against PAR-1 receptor. Some of these analogues showed activities and rat plasma levels comparable to vorapaxar. Compound 5c from this series showed excellent PAR-1 activity (K i = 5.1 nM). We also present a model of these spirocyclic compounds docked to the PAR-1 receptor based on the X-ray crystal structure of vorapaxar bound to PAR-1 receptor. This model explains some of the structure-activity relationships in this series. PMID:24900880

Chelliah, Mariappan V; Eagen, Keith; Guo, Zhuyan; Chackalamannil, Samuel; Xia, Yan; Tsai, Hsingan; Greenlee, William J; Ahn, Ho-Sam; Kurowski, Stan; Boykow, George; Hsieh, Yunsheng; Chintala, Madhu

2014-05-01

378

Excited state properties of a short ?-electron conjugated peridinin analogue  

PubMed Central

C29-peridinin is a synthetic analogue of the important, naturally-occurring carotenoid, peridinin, found in several marine algal species. C29-peridinin has five conjugated carbon-carbon double bonds compared to eight possessed by peridinin and also lacks the methyl group functionalities typically present along the polyene chain of carotenoids. These structural modifications lead to unique excited state properties and important insights regarding the factors controlling the photophysics of peridinin and other carbonyl-containing carotenoids, which are critical components of the light-harvesting systems of many photosynthetic organisms. PMID:24678069

Magdaong, Nikki M.; Niedzwiedzki, Dariusz M.; Greco, Jordan A.; Liu, Hongbin; Yano, Koki; Kajikawa, Takayuki; Sakaguchi, Kazuhiko; Katsumura, Shigeo; Birge, Robert R.; Frank, Harry A.

2014-01-01

379

Synthesis, Preliminary Bioevaluation and Computational Analysis of Caffeic Acid Analogues  

PubMed Central

A series of caffeic acid amides were designed, synthesized and evaluated for anti-inflammatory activity. Most of them exhibited promising anti-inflammatory activity against nitric oxide (NO) generation in murine macrophage RAW264.7 cells. A 3D pharmacophore model was created based on the biological results for further structural optimization. Moreover, predication of the potential targets was also carried out by the PharmMapper server. These amide analogues represent a promising class of anti-inflammatory scaffold for further exploration and target identification. PMID:24857914

Liu, Zhiqian; Fu, Jianjun; Shan, Lei; Sun, Qingyan; Zhang, Weidong

2014-01-01

380

Methylation of desmethyl analogue of Y nucleosides. Wyosine from guanosine.  

PubMed Central

Wyosine la, one of the fluorescent hypermodified Y nucleosides found in tRNAsPhe, was synthesized chemically from its biogenetic precursor guanosine 2. The route involved transformation of 2 into the tricyclic structure 3a and subsequent methylation at N-4. The major products of various methylation procedures were isomers of wyosine, methylated at N-5 (3b) or at N-1 (4). Mesoionic compound 4 is a new analogue of 7-methylguanosine 5, modified nucleoside occurring in the unique positions in transfer, messenger and ribosomal RNAs. The chromatographic and spectral characteristics of wyosine and its isomers is given. PMID:6192396

Golankiewicz, B; Folkman, W

1983-01-01

381

Structuralism.  

ERIC Educational Resources Information Center

Provided is an overview of the analytical method known as structuralism. The first chapter discusses the three key components of the concept of a structure: the view of a system as a whole instead of so many parts; the study of the transformations in the system; and the fact that these transformations never lead beyond the system but always…

Piaget, Jean

382

Analogues of the Inhoffen-Lythgoe diol with anti-proliferative activity.  

PubMed

The anti-proliferative activity of a series of ester- and amide-linked Inhoffen-Lythgoe side chain analogues is reported. Whereas the Inhoffen-Lythgoe diol was inactive in these studies, a number of aromatic and aliphatic ester-linked side chains demonstrated modest in vitro growth inhibition in two human cancepar cell lines, U87MG (glioblastoma) and HT-29 (colorectal adenocarcinoma). Structure-activity relationship (SAR) studies demonstrated the most active aromatic (13) and aliphatic (25 and 29) substituted analogues were approximately equipotent in U87MG and HT-29 cells. Further evaluation of 13, 25, and 29 indicated these analogues do not activate canonical vitamin D signaling nor antagonize Hedgehog (Hh) signaling. Thus, the cellular mechanism(s) that govern the anti-proliferative activity for this class of truncated vitamin D-based structures appears to be different from classical mechanisms previously identified for these scaffolds. PMID:23972439

DeBerardinis, Albert M; Lemieux, Steven; Hadden, M Kyle

2013-10-01

383

Identification and structural mechanism for a novel interaction between a ubiquitin ligase WWP1 and Nogo-A, a key inhibitor for central nervous system regeneration.  

PubMed

Nogo-A has been extensively demonstrated to play key roles in inhibiting central nervous system regeneration, regulating endoplasmic reticulum formation, and maintaining the integrity of the neuromuscular junction. In this study, an E3 ubiquitin ligase WWP1 was first identified to be a novel interacting partner for Nogo-A both in vitro and in vivo. By using CD, ITC, and NMR, we have further conducted extensive studies on all four WWP1 WW domains and their interactions with a Nogo-A peptide carrying the only PPxY motif. The results lead to several striking findings. (1) Despite containing an unstructured region, the 186-residue WWP1 fragment containing all four WW domains is able to interact with the Nogo-A(650-666) peptide with a high affinity, with a dissociation constant (K(d)) of 1.68 microM. (2) Interestingly, four isolated WW domains show differential structural properties in the free states. WW1 and WW2 are only partially folded, while WW4 is well-folded. Nevertheless, they all become well-folded upon binding to Nogo-A(650-666), with K(d) values ranging from 1.03 to 3.85 microM. (3) The solution structure of the best-folded WW4 domain is determined, and the binding-perturbed residues were derived for both WW4 and Nogo-A(650-666) by NMR HSQC titrations. Moreover, on the basis of the NMR data, the complex model is constructed by HADDOCK 2.0. This study provides rationales as well as a template Nogo-A(650-666) for further design of molecules to intervene in the WWP1-Nogo-A interaction which may regulate the Nogo-A protein level by controlling its ubiquitination. PMID:19035836

Qin, Haina; Pu, Helen X; Li, Minfen; Ahmed, Sohail; Song, Jianxing

2008-12-23

384

Review of Current State of the Art and Key Design Issues With Potential Solutions for Liquid Hydrogen Cryogenic Storage Tank Structures for Aircraft Applications  

NASA Technical Reports Server (NTRS)

Due to its high specific energy content, liquid hydrogen (LH2) is emerging as an alternative fuel for future aircraft. As a result, there is a need for hydrogen tank storage systems, for these aircraft applications, that are expected to provide sufficient capacity for flight durations ranging from a few minutes to several days. It is understood that the development of a large, lightweight, reusable cryogenic liquid storage tank is crucial to meet the goals of and supply power to hydrogen-fueled aircraft, especially for long flight durations. This report provides an annotated review (including the results of an extensive literature review) of the current state of the art of cryogenic tank materials, structural designs, and insulation systems along with the identification of key challenges with the intent of developing a lightweight and long-term storage system for LH2. The broad classes of insulation systems reviewed include foams (including advanced aerogels) and multilayer insulation (MLI) systems with vacuum. The MLI systems show promise for long-term applications. Structural configurations evaluated include single- and double-wall constructions, including sandwich construction. Potential wall material candidates are monolithic metals as well as polymer matrix composites and discontinuously reinforced metal matrix composites. For short-duration flight applications, simple tank designs may suffice. Alternatively, for longer duration flight applications, a double-wall construction with a vacuum-based insulation system appears to be the most optimum design. The current trends in liner material development are reviewed in the case that a liner is required to minimize or eliminate the loss of hydrogen fuel through permeation.

Mital, Subodh K.; Gyekenyesi, John Z.; Arnold, Steven M.; Sullivan, Roy M.; Manderscheid, Jane M.; Murthy, Pappu L. N.

2006-01-01

385

Quantitative comparisons of analogue models of brittle wedge dynamics  

NASA Astrophysics Data System (ADS)

Analogue model experiments are widely used to gain insights into the evolution of geological structures. In this study, we present a direct comparison of experimental results of 14 analogue modelling laboratories using prescribed set-ups. A quantitative analysis of the results will document the variability among models and will allow an appraisal of reproducibility and limits of interpretation. This has direct implications for comparisons between structures in analogue models and natural field examples. All laboratories used the same frictional analogue materials (quartz and corundum sand) and prescribed model-building techniques (sieving and levelling). Although each laboratory used its own experimental apparatus, the same type of self-adhesive foil was used to cover the base and all the walls of the experimental apparatus in order to guarantee identical boundary conditions (i.e. identical shear stresses at the base and walls). Three experimental set-ups using only brittle frictional materials were examined. In each of the three set-ups the model was shortened by a vertical wall, which moved with respect to the fixed base and the three remaining sidewalls. The minimum width of the model (dimension parallel to mobile wall) was also prescribed. In the first experimental set-up, a quartz sand wedge with a surface slope of ˜20° was pushed by a mobile wall. All models conformed to the critical taper theory, maintained a stable surface slope and did not show internal deformation. In the next two experimental set-ups, a horizontal sand pack consisting of alternating quartz sand and corundum sand layers was shortened from one side by the mobile wall. In one of the set-ups a thin rigid sheet covered part of the model base and was attached to the mobile wall (i.e. a basal velocity discontinuity distant from the mobile wall). In the other set-up a basal rigid sheet was absent and the basal velocity discontinuity was located at the mobile wall. In both types of experiments, models accommodated initial shortening by a forward- and a backward-verging thrust. Further shortening was taken up by in-sequence formation of forward-verging thrusts. In all experiments, boundary stresses created significant drag of structures along the sidewalls. We therefore compared the surface slope and the location, dip angle and spacing of thrusts in sections through the central part of the model. All models show very similar cross-sectional evolutions demonstrating reproducibility of first-order experimental observations. Nevertheless, there are significant along-strike variations of structures in map view highlighting the limits of interpretations of analogue model results. These variations may be related to the human factor, differences in model width and/or differences in laboratory temperature and especially humidity affecting the mechanical properties of the granular materials. GeoMod2008 Analogue Team: Susanne Buiter, Caroline Burberry, Jean-Paul Callot, Cristian Cavozzi, Mariano Cerca, Ernesto Cristallini, Alexander Cruden, Jian-Hong Chen, Leonardo Cruz, Jean-Marc Daniel, Victor H. Garcia, Caroline Gomes, Céline Grall, Cecilia Guzmán, Triyani Nur Hidayah, George Hilley, Chia-Yu Lu, Matthias Klinkmüller, Hemin Koyi, Jenny Macauley, Bertrand Maillot, Catherine Meriaux, Faramarz Nilfouroushan, Chang-Chih Pan, Daniel Pillot, Rodrigo Portillo, Matthias Rosenau, Wouter P. Schellart, Roy Schlische, Andy Take, Bruno Vendeville, Matteo Vettori, M. Vergnaud, Shih-Hsien Wang, Martha Withjack, Daniel Yagupsky, Yasuhiro Yamada

Schreurs, Guido

2010-05-01

386

Theoretical study on absorption and emission spectra of pyrrolo-C analogues  

NASA Astrophysics Data System (ADS)

Fluorescent nucleoside analogues have attracted much attention in studying the structure and dynamics of nucleic acids in recent years. In the present work, we use theoretical calculations to investigate the structural and optical properties of Pyrrolo-C (PyC) and its analogues which are modified via the conjugation or fusion of different aromatic ring to the PyC core. We also consider the effects of aqueous solution and base pairing. The results show that the fluorescent pyrrolo-C analogues can pair with guanosine to form stable H-bonded WC base pairs. The calculated absorption peaks of modified deoxyribonucleosides agree well with the measured data. The absorption and emission maxima of the pyrrolo-C analogues are greatly red shifted compared with nature C. The solvent effects can induce wavelength blue shift a