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Sample records for nendo chinetsu kaihatsu

  1. Crystal Structure of a Monomeric Form of Severe Acute Respiratory Syndrome Coronavirus Endonuclease Nsp15 Suggests a Role for Hexamerization As An Allosteric Switch

    SciTech Connect

    Joseph, J.S.; Saikatendu, K.S.; Subramanian, V.; Neuman, B.W.; Buchmeier, M.J.; Stevens, R.C.; Kuhn, P.; /Scripps Res. Inst.

    2007-07-09

    Mature nonstructural protein-15 (nsp15) from the severe acute respiratory syndrome coronavirus (SARS-CoV) contains a novel uridylate-specific Mn{sup 2+}-dependent endoribonuclease (NendoU). Structure studies of the full-length form of the obligate hexameric enzyme from two CoVs, SARS-CoV and murine hepatitis virus, and its monomeric homologue, XendoU from Xenopus laevis, combined with mutagenesis studies have implicated several residues in enzymatic activity and the N-terminal domain as the major determinant of hexamerization. However, the tight link between hexamerization and enzyme activity in NendoUs has remained an enigma. Here, we report the structure of a trimmed, monomeric form of SARS-CoV nsp15 (residues 28 to 335) determined to a resolution of 2.9 Angstroms. The catalytic loop (residues 234 to 249) with its two reactive histidines (His 234 and His 249) is dramatically flipped by {approx}120 degrees into the active site cleft. Furthermore, the catalytic nucleophile Lys 289 points in a diametrically opposite direction, a consequence of an outward displacement of the supporting loop (residues 276 to 295). In the full-length hexameric forms, these two loops are packed against each other and are stabilized by intimate intersubunit interactions. Our results support the hypothesis that absence of an adjacent monomer due to deletion of the hexamerization domain is the most likely cause for disruption of the active site, offering a structural basis for why only the hexameric form of this enzyme is active.

  2. The nonstructural protein 11 of porcine reproductive and respiratory syndrome virus inhibits NF-κB signaling by means of its deubiquitinating activity.

    PubMed

    Wang, Dang; Fan, Jinxiu; Fang, Liurong; Luo, Rui; Ouyang, Haiping; Ouyang, Chao; Zhang, Huan; Chen, Huanchun; Li, Kui; Xiao, Shaobo

    2015-12-01

    Since its emergence in the late 1980s, porcine reproductive and respiratory syndrome (PRRS) has been devastating the swine industry worldwide. The causative agent is an Arterivirus, referred to as PRRS virus (PRRSV). The pathogenic mechanisms of PRRS are poorly understood, but are believed to correlate with the ability of PRRSV to inhibit immune responses of the host. However, precisely how the virus is capable of doing so remains obscure. In this study, we showed that PRRSV infection led to reduced ubiquitination of cellular proteins. Screening all of the 12 nonstructural proteins (Nsps) encoded by PRRSV revealed that, apart from the Nsp2 which contains the deubiqintinating (DUB) ovarian tumor (OTU) domain, Nsp11, which encodes a unique and conserved endoribonuclease (NendoU) throughout the Nidovirus order, also possesses DUB activity. In vivo assay demonstrated that Nsp11 specifically removed lysine 48 (K48)-linked polyubiquitin chains and the conserved sites C112, H144, D173, K180, and Y219 were critical for its DUB activity. Remarkably, DUB activity was responsible for the capacity of Nsp11 to inhibit nuclear factor κB (NF-κB) activation. Mutations abrogating the DUB activity of Nsp11 toward K48-linked polyubiquitin chains of IκBα nullified the suppressive effect on NF-κB. Our data add Nsp11 to the list of DUBs encoded by PRRSV and uncover a novel mechanism by which PRRSV cripples host innate immune responses. PMID:26342881

  3. Discovery of a novel nidovirus in cattle with respiratory disease

    PubMed Central

    Sameroff, Stephen; Hesse, Richard A.; Hause, Ben M.; Desai, Aaloki; Jain, Komal; Ian Lipkin, W.

    2015-01-01

    The family Coronaviridae represents a diverse group of vertebrate RNA viruses, all with genomes greater than 26 000 nt. Here, we report the discovery and genetic characterization of a novel virus present in cattle with respiratory disease. Phylogenetic characterization of this virus revealed that it clusters within the subfamily Torovirinae, in the family Coronaviridae. The complete genome consists of only 20 261 nt and represents the smallest reported coronavirus genome. We identified seven ORFs, including the canonical nidovirus ORF1a and ORF1b. Analysis of polyprotein 1ab revealed that this virus, tentatively named bovine nidovirus (BoNV), shares the highest homology with the recently described python-borne nidoviruses and contains several conserved nidovirus motifs, but does not encode the NendoU or O-MT domains that are present in other viruses within the family Coronaviridae. In concert with its reduced genome, the atypical domain architecture indicates that this virus represents a unique lineage within the order Nidovirales. PMID:25918239

  4. Source of the 6 February 2013 Mw = 8.0 Santa Cruz Islands Tsunami

    NASA Astrophysics Data System (ADS)

    Romano, F.; Molinari, I.; Lorito, S.; Piatanesi, A.

    2015-06-01

    On 6 February 2013 an Mw = 8.0 subduction earthquake occurred close to Santa Cruz Islands at the transition between the Solomon and the New Hebrides Trench. The ensuing tsunami caused significant inundation on the closest Nendo Island. The seismic source was studied with teleseismic broadband P-wave inversion optimized with tsunami forward modelling at DART buoys (Lay et al., 2013) and with inversion of teleseismic body and surface waves (Hayes et al., 2014a). The two studies also use different hypocentres and different planar fault models and found quite different slip models. In particular, Hayes et al. (2014a) argued for an aseismic slip patch SE from the hypocentre. We here develop a 3-D model of the fault surface from seismicity analysis and retrieve the tsunami source by inverting DART and tide-gauge data. Our tsunami source model features a main slip patch (peak value of ~ 11 m) SE of the hypocentre and reaching the trench. The rake direction is consistent with the progressively more oblique plate convergence towards the Solomon trench. The tsunami source partially overlaps the hypothesized aseismic slip area, which then might have slipped coseismically.

  5. Source of the 6 February 2013 Mw 8.0 Santa Cruz Islands Tsunami

    NASA Astrophysics Data System (ADS)

    Romano, F.; Molinari, I.; Lorito, S.; Piatanesi, A.

    2015-03-01

    On 6 February 2013 an Mw 8.0 subduction earthquake occurred close to Santa Cruz Islands at the transition between the Solomon and the New Hebrides Trench. The ensuing tsunami caused significant inundation on the closest Nendo Island. The seismic source was studied with teleseismic broadband P waves inversion optimized with tsunami forward modeling at DART buoys (Lay et al., 2013), and with inversion of teleseismic body and surface waves (Hayes et al., 2014). The two studies also use different hypocenters and different planar fault models, and found quite different slip models. In particular, Hayes et al. (2014) argued for an aseismic slip patch SE from the hypocenter. We here develop a 3-D model of the fault surface from seismicity analysis and retrieve the tsunami source by inverting DART and tide-gauge data. Our tsunami source model features a main slip patch (peak value of ~11 m) SE of the hypocentre, and reaching to the trench. The rake direction is consistent with the progressively more oblique plate convergence towards the Solomon trench. The tsunami source partially overlaps the hypothesized aseismic slip area, which then might have slipped coseismically.

  6. Source of the 6 February 2013 Mw 8.0 Santa Cruz Islands Tsunami.

    NASA Astrophysics Data System (ADS)

    Romano, F.; Molinari, I.; Lorito, S.; Piatanesi, A.

    2014-12-01

    On February 6, 2013 a Mw8.0 interplate earthquake occurred in the Santa Cruz Islands region. The epicenter is located near a complex section of the Australia-Pacific plate boundary, where a short segment of dominantly strike-slip plate motion links the Solomon Trench to the New Hebrides Trench. In this region, the Australia plate subducts beneath the Pacific plate with a convergence rate of ~9cm/yr. This earthquake generated a tsunami that struck the city of Lata and several villages located on the Nendo island with tsunami height exceeding 11m (Fritz et al.,2014). The tsunami has been distinctly recorded by 5 DART buoys in the Pacific Ocean and by some tide-gauges at Solomon Islands, Fiji Islands, and New Caledonia. In this work we retrieve the source of the tsunami by inverting the signals recorded by both DART buoys and tide-gauges, and using an earthquake fault model that accounts for the variability of the subduction plate geometry. We compare and discuss our tsunamigenic slip model with previous coseismic slip models obtained by teleseismic data (Hayes et al.,2013) and telesismic data constrained by tsunami records (Lay et al.,2013). Our preferred tsunami source (maximum slip value of ~10m) is located southeast from the hypocenter and the slip direction is in agreement with the convergence direction that becomes progressively more oblique in the NW segment. We find a tsunami source roughly consistent to a possible source of low frequency radiation (http://www.iris.edu/spud/backprojection) and/or to the region of aseismic slip argued by Hayes et al. (2013). However, we do not find significantly tsunamigenic slip in the region of seismic high frequency radiation around the hypocenter.

  7. Isolation and Characterization of a Novel Betacoronavirus Subgroup A Coronavirus, Rabbit Coronavirus HKU14, from Domestic Rabbits

    PubMed Central

    Lau, Susanna K. P.; Woo, Patrick C. Y.; Yip, Cyril C. Y.; Fan, Rachel Y. Y.; Huang, Yi; Wang, Ming; Guo, Rongtong; Lam, Carol S. F.; Tsang, Alan K. L.; Lai, Kenneth K. Y.; Chan, Kwok-Hung; Che, Xiao-Yan; Zheng, Bo-Jian

    2012-01-01

    We describe the isolation and characterization of a novel Betacoronavirus subgroup A coronavirus, rabbit coronavirus HKU14 (RbCoV HKU14), from domestic rabbits. The virus was detected in 11 (8.1%) of 136 rabbit fecal samples by reverse transcriptase PCR (RT-PCR), with a viral load of up to 108 copies/ml. RbCoV HKU14 was able to replicate in HRT-18G and RK13 cells with cytopathic effects. Northern blotting confirmed the production of subgenomic mRNAs coding for the HE, S, NS5a, E, M, and N proteins. Subgenomic mRNA analysis revealed a transcription regulatory sequence, 5′-UCUAAAC-3′. Phylogenetic analysis showed that RbCoV HKU14 formed a distinct branch among Betacoronavirus subgroup A coronaviruses, being most closely related to but separate from the species Betacoronavirus 1. A comparison of the conserved replicase domains showed that RbCoV HKU14 possessed <90% amino acid identities to most members of Betacoronavirus 1 in ADP-ribose 1″-phosphatase (ADRP) and nidoviral uridylate-specific endoribonuclease (NendoU), indicating that RbCoV HKU14 should represent a separate species. RbCoV HKU14 also possessed genomic features distinct from those of other Betacoronavirus subgroup A coronaviruses, including a unique NS2a region with a variable number of small open reading frames (ORFs). Recombination analysis revealed possible recombination events during the evolution of RbCoV HKU14 and members of Betacoronavirus 1, which may have occurred during cross-species transmission. Molecular clock analysis using RNA-dependent RNA polymerase (RdRp) genes dated the most recent common ancestor of RbCoV HKU14 to around 2002, suggesting that this virus has emerged relatively recently. Antibody against RbCoV was detected in 20 (67%) of 30 rabbit sera tested by an N-protein-based Western blot assay, whereas neutralizing antibody was detected in 1 of these 20 rabbits. PMID:22398294

  8. A Dimerization-Dependent Mechanism Drives the Endoribonuclease Function of Porcine Reproductive and Respiratory Syndrome Virus nsp11

    PubMed Central

    Shi, Yuejun; Li, Youwen; Lei, Yingying; Ye, Gang; Shen, Zhou; Sun, Limeng; Luo, Rui; Wang, Dang; Fu, Zhen F.; Xiao, Shaobo

    2016-01-01

    structural analysis revealed NendoU active site residues, which are conserved throughout the order Nidovirales (families Arteriviridae and Coronaviridae) and the major determinants of dimerization (Ser74 and Phe76) in Arteriviridae. Importantly, these findings may provide a new structural basis for antiviral drug development. PMID:26912626