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dc.contributor.authorHiguera, Ignacio de laes_ES
dc.contributor.authorFerrer-Orta, Cristinaes_ES
dc.contributor.authorMoreno, Elenaes_ES
dc.contributor.authorÁvila, Ana Isabel dees_ES
dc.contributor.authorSoria, María Eugeniaes_ES
dc.contributor.authorSingh, Kamalendraes_ES
dc.contributor.authorFlavia Caridi,es_ES
dc.contributor.authorSobrino Castelló, Franciscoes_ES
dc.contributor.authorSarafianos, Stefan G.es_ES
dc.contributor.authorPerales, Celiaes_ES
dc.contributor.authorVerdaguer, Núriaes_ES
dc.contributor.authorDomingo, Estebanes_ES
dc.date.accessioned2019-01-16T12:31:21Z-
dc.date.available2019-01-16T12:31:21Z-
dc.date.issued2018-10-
dc.identifier.citationJournal of Virology 92(20): e01119-18 (2018)es_ES
dc.identifier.issn0022-538X-
dc.identifier.urihttp://hdl.handle.net/10261/174186-
dc.description.abstractViral RNA-dependent RNA polymerases (RdRps) are major determinants of high mutation rates and generation of mutant spectra that mediate RNA virus adaptability. The RdRp of the picornavirus foot-and-mouth disease virus (FMDV), termed 3D, is a multifunctional protein that includes a nuclear localization signal (NLS) in its N-terminal region. Previous studies documented that some amino acid substitutions within the NLS altered nucleotide recognition and enhanced the incorporation of the mutagenic purine analogue ribavirin in viral RNA, but the mutants tested were not viable and their response to lethal mutagenesis could not be studied. Here we demonstrate that NLS amino acid substitution M16A of FMDV serotype C does not affect infectious virus production but accelerates ribavirin-mediated virus extinction. The mutant 3D displays polymerase activity, RNA binding, and copying processivity that are similar to those of the wild-type enzyme but shows increased ribavirin-triphosphate incorporation. Crystal structures of the mutant 3D in the apo and RNA-bound forms reveal an expansion of the template entry channel due to the replacement of the bulky Met by Ala. This is a major difference with other 3D mutants with altered nucleotide analogue recognition. Remarkably, two distinct loop β9-α11 conformations distinguish 3Ds that exhibit higher or lower ribavirin incorporation than the wild-type enzyme. This difference identifies a specific molecular determinant of ribavirin sensitivity of FMDV. Comparison of several polymerase mutants indicates that different domains of the molecule can modify nucleotide recognition and response to lethal mutagenesis. The connection of this observation with current views on quasispecies adaptability is discussed.es_ES
dc.description.sponsorshipWork in Madrid was supported by grants BFU2011-23604, SAF2014-52400-R, and AGL2014-52395-C2-1-R from the Spanish MINECO and S2013/ABI-2906 (PLATESA from Comunidad de Madrid/FEDER). CIBERehd (Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas) is funded by Instituto de Salud Carlos III. Work in Barcelona was supported by grants BIO2017-83906-P and Maria de Maeztu Unit of Excellence MDM-2014-0435, from the Spanish MINECO. X-ray data were collected at ALBA Synchrotron (Cerdanyola de Valles, Spain) XALOC beamline with the collaboration of ALBA staff and at ESRF beamline ID29 (Grenoble, France). Financial support was provided by ALBA and ESRF. The kinetic studies at the University of Missouri were partially supported by grant AI076119 (National Institutes of Health, USA) to S.G.S. C.P. is supported by the Miguel Servet program of the Instituto de Salud Carlos III (CP14/ 00121) cofinanced by the European Regional Development Fund (ERDF). Institutional grants from the Fundación Ramón Areces and Banco Santander to the CBMSO are also acknowledged.es_ES
dc.language.isoenges_ES
dc.publisherAmerican Society for Microbiologyes_ES
dc.relationBIO2017-83906-P/AEI/10.13039/501100011033-
dc.relationinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2014-52400-Res_ES
dc.relationinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/AGL2014-52395-C2-1-Res_ES
dc.relationS2013/ABI-2906/PLATESA-CMes_ES
dc.relationinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/BIO2017-83906-Pes_ES
dc.relationinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/MDM-2014-0435es_ES
dc.relation.isversionofPostprint-
dc.rightsopenAccessen_EN
dc.subjectViral quasispecieses_ES
dc.subjectNucleotide recognitiones_ES
dc.subjectPolymerase structurees_ES
dc.subjectRibavirines_ES
dc.subjectError thresholdes_ES
dc.subjectAntiviral therapyes_ES
dc.titleContribution of a multifunctional polymerase region of foot-and-mouth disease virus to lethal mutagenesises_ES
dc.typeartículoes_ES
dc.identifier.doi10.1128/JVI.01119-18-
dc.description.peerreviewedPeer reviewedes_ES
dc.relation.publisherversionhttps://doi.org/10.1128/JVI.01119-18es_ES
dc.identifier.e-issn1098-5514-
dc.contributor.funderMinisterio de Economía y Competitividad (España)es_ES
dc.contributor.funderAgencia Estatal de Investigación (España)-
dc.contributor.funderComunidad de Madrides_ES
dc.contributor.funderEuropean Commissiones_ES
dc.contributor.funderCentro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España)es_ES
dc.contributor.funderInstituto de Salud Carlos IIIes_ES
dc.contributor.funderALBA Synchrotrones_ES
dc.contributor.funderEuropean Synchrotron Radiation Facilityes_ES
dc.contributor.funderNational Institutes of Health (US)es_ES
dc.contributor.funderFundación Ramón Areceses_ES
dc.contributor.funderFundación Banco Santanderes_ES
dc.relation.csices_ES
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dc.identifier.funderhttp://dx.doi.org/10.13039/501100003329es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100004587es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/100008049es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/100008054es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/100000002es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100001671es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100000780es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100011033es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/100012818es_ES
dc.identifier.pmid30068642-
dc.type.coarhttp://purl.org/coar/resource_type/c_6501es_ES
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