Structural and molecular basis of mismatch correction and ribavirin excision from coronavirus RNA
Identifieur interne : 001439 ( Pmc/Curation ); précédent : 001438; suivant : 001440Structural and molecular basis of mismatch correction and ribavirin excision from coronavirus RNA
Auteurs : François Ferron [France] ; Lorenzo Subissi [France] ; Ana Theresa Silveira De Morais [France] ; Nhung Thi Tuyet Le [France] ; Marion Sevajol [France] ; Laure Gluais [France] ; Etienne Decroly [France] ; Clemens Vonrhein ; Gérard Bricogne ; Bruno Canard [France] ; Isabelle Imbert [France]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2017.
Abstract
Emerging coronaviruses (CoVs; severe acute respiratory syndrome-CoV and Middle East respiratory syndrome-CoV) pose serious health threats globally, with no specific antiviral treatments available. These viruses are able to faithfully synthesize their large genomic RNA. We report, however, that their main RNA polymerase, nsp12, is not accurate. To achieve accuracy, CoVs have acquired nsp14, a bifunctional enzyme able to methylate the viral RNA cap [methyltransferase (MTase)] and excise erroneous mutagenic nucleotides inserted by nsp12. Strikingly, ribavirin can be excised from the viral genome, thus showing no antiviral activity. The crystal structure of nsp14 shows that it is unique, having been replaced by other MTase types during evolution. This unprecedented RNA correction machinery has allowed RNA genome size expansion, but also provided potential nucleoside drug resistance to these deadly pathogens.
Url:
DOI: 10.1073/pnas.1718806115
PubMed: 29279395
PubMed Central: 5777078
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Clemens Vonrhein<affiliation><nlm:aff id="aff2"><institution>Global Phasing Ltd.</institution>, Cambridge CB3 0AX,<country>England</country></nlm:aff><wicri:noCountry code="nlm country">England</wicri:noCountry></affiliation><affiliation><nlm:aff id="aff2"><institution>Global Phasing Ltd.</institution>, Cambridge CB3 0AX,<country>England</country></nlm:aff><wicri:noCountry code="nlm country">England</wicri:noCountry></affiliation>Le document en format XML
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sort="Decroly, Etienne" uniqKey="Decroly E" first="Etienne" last="Decroly">Etienne Decroly</name><affiliation wicri:level="1"><nlm:aff id="aff1">Centre National de la Recherche Scientifique,<institution>Aix-Marseille Université</institution>, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 13009 Marseille,<country>France</country>;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Vonrhein, Clemens" sort="Vonrhein, Clemens" uniqKey="Vonrhein C" first="Clemens" last="Vonrhein">Clemens Vonrhein</name><affiliation><nlm:aff id="aff2"><institution>Global Phasing Ltd.</institution>, Cambridge CB3 0AX,<country>England</country></nlm:aff><wicri:noCountry code="nlm country">England</wicri:noCountry></affiliation></author><author><name sortKey="Bricogne, Gerard" sort="Bricogne, Gerard" uniqKey="Bricogne G" first="Gérard" last="Bricogne">Gérard Bricogne</name><affiliation><nlm:aff id="aff2"><institution>Global Phasing Ltd.</institution>, Cambridge CB3 0AX,<country>England</country></nlm:aff><wicri:noCountry code="nlm country">England</wicri:noCountry></affiliation></author><author><name sortKey="Canard, Bruno" sort="Canard, Bruno" uniqKey="Canard B" first="Bruno" last="Canard">Bruno Canard</name><affiliation wicri:level="1"><nlm:aff id="aff1">Centre National de la Recherche Scientifique,<institution>Aix-Marseille Université</institution>, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 13009 Marseille,<country>France</country>;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Imbert, Isabelle" sort="Imbert, Isabelle" uniqKey="Imbert I" first="Isabelle" last="Imbert">Isabelle Imbert</name><affiliation wicri:level="1"><nlm:aff id="aff1">Centre National de la Recherche Scientifique,<institution>Aix-Marseille Université</institution>, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 13009 Marseille,<country>France</country>;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Significance</title><p>Emerging coronaviruses (CoVs; severe acute respiratory syndrome-CoV and Middle East respiratory syndrome-CoV) pose serious health threats globally, with no specific antiviral treatments available. These viruses are able to faithfully synthesize their large genomic RNA. We report, however, that their main RNA polymerase, nsp12, is not accurate. To achieve accuracy, CoVs have acquired nsp14, a bifunctional enzyme able to methylate the viral RNA cap [methyltransferase (MTase)] and excise erroneous mutagenic nucleotides inserted by nsp12. Strikingly, ribavirin can be excised from the viral genome, thus showing no antiviral activity. The crystal structure of nsp14 shows that it is unique, having been replaced by other MTase types during evolution. This unprecedented RNA correction machinery has allowed RNA genome size expansion, but also provided potential nucleoside drug resistance to these deadly pathogens.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Drake, Jw" uniqKey="Drake J">JW Drake</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Belshaw, R" uniqKey="Belshaw R">R Belshaw</name></author><author><name sortKey="Gardner, A" uniqKey="Gardner A">A Gardner</name></author><author><name sortKey="Rambaut, A" uniqKey="Rambaut A">A Rambaut</name></author><author><name sortKey="Pybus, Og" uniqKey="Pybus O">OG Pybus</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sanjuan, R" uniqKey="Sanjuan R">R Sanjuán</name></author><author><name sortKey="Nebot, Mr" uniqKey="Nebot M">MR Nebot</name></author><author><name sortKey="Chirico, N" uniqKey="Chirico N">N Chirico</name></author><author><name sortKey="Mansky, Lm" 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id><journal-id journal-id-type="iso-abbrev">Proc. Natl. Acad. Sci. U.S.A</journal-id><journal-id journal-id-type="hwp">pnas</journal-id><journal-id journal-id-type="pmc">pnas</journal-id><journal-id journal-id-type="publisher-id">PNAS</journal-id><journal-title-group><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title></journal-title-group><issn pub-type="ppub">0027-8424</issn><issn pub-type="epub">1091-6490</issn><publisher><publisher-name>National Academy of Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">29279395</article-id><article-id pub-id-type="pmc">5777078</article-id><article-id pub-id-type="publisher-id">201718806</article-id><article-id pub-id-type="doi">10.1073/pnas.1718806115</article-id><article-categories><subj-group subj-group-type="hwp-journal-coll"><subject>530</subject></subj-group><subj-group subj-group-type="heading"><subject>PNAS Plus</subject></subj-group><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Biochemistry</subject></subj-group></subj-group><series-title>PNAS Plus</series-title></article-categories><title-group><article-title>Structural and molecular basis of mismatch correction and ribavirin excision from coronavirus RNA</article-title><alt-title alt-title-type="short">Mismatch and ribavirin excisions from viral RNA</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Ferron</surname><given-names>François</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Subissi</surname><given-names>Lorenzo</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Silveira De Morais</surname><given-names>Ana Theresa</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Le</surname><given-names>Nhung Thi Tuyet</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sevajol</surname><given-names>Marion</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gluais</surname><given-names>Laure</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Decroly</surname><given-names>Etienne</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Vonrhein</surname><given-names>Clemens</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bricogne</surname><given-names>Gérard</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Canard</surname><given-names>Bruno</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="author-notes" rid="fn2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">http://orcid.org/0000-0001-5630-9945</contrib-id><name><surname>Imbert</surname><given-names>Isabelle</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="author-notes" rid="fn2"><sup>2</sup></xref><xref ref-type="corresp" rid="cor1"><sup>3</sup></xref></contrib><aff id="aff1"><sup>a</sup>Centre National de la Recherche Scientifique,<institution>Aix-Marseille Université</institution>, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 13009 Marseille,<country>France</country>;</aff><aff id="aff2"><sup>b</sup><institution>Global Phasing Ltd.</institution>, Cambridge CB3 0AX,<country>England</country></aff></contrib-group><author-notes><corresp id="cor1"><sup>3</sup>To whom correspondence should be addressed. Email: <email>isabelle.imbert@univ-amu.fr</email>.</corresp><fn fn-type="edited-by"><p>Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved December 1, 2017 (received for review October 30, 2017)</p></fn><fn fn-type="con"><p>Author contributions: F.F., L.S., A.T.S.D.M., B.C., and I.I. designed research; F.F., L.S., A.T.S.D.M., N.T.T.L., M.S., L.G., and I.I. performed research; C.V. and G.B. contributed new reagents/analytic tools; F.F., L.S., A.T.S.D.M., E.D., C.V., G.B., B.C., and I.I. analyzed data; and F.F., L.S., A.T.S.D.M., B.C., and I.I. wrote the paper.</p></fn><fn fn-type="equal" id="fn1"><p><sup>1</sup>F.F., L.S., and A.T.S.D.M. contributed equally to this work.</p></fn><fn fn-type="equal" id="fn2"><p><sup>2</sup>B.C. and I.I. contributed equally to this work.</p></fn></author-notes><pub-date pub-type="ppub"><day>9</day><month>1</month><year>2018</year></pub-date><pub-date pub-type="epub"><day>26</day><month>12</month><year>2017</year></pub-date><pub-date pub-type="pmc-release"><day>26</day><month>12</month><year>2017</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>115</volume><issue>2</issue><fpage>E162</fpage><lpage>E171</lpage><permissions><copyright-statement>Copyright © 2018 the Author(s). Published by PNAS.</copyright-statement><copyright-year>2018</copyright-year><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><ali:license_ref specific-use="vor">https://creativecommons.org/licenses/by/4.0/</ali:license_ref><license-p>This open access article is distributed under <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License 4.0 (CC BY)</ext-link>.</license-p></license></permissions><self-uri xlink:title="pdf" xlink:href="pnas.201718806.pdf"></self-uri><abstract abstract-type="executive-summary"><title>Significance</title><p>Emerging coronaviruses (CoVs; severe acute respiratory syndrome-CoV and Middle East respiratory syndrome-CoV) pose serious health threats globally, with no specific antiviral treatments available. These viruses are able to faithfully synthesize their large genomic RNA. We report, however, that their main RNA polymerase, nsp12, is not accurate. To achieve accuracy, CoVs have acquired nsp14, a bifunctional enzyme able to methylate the viral RNA cap [methyltransferase (MTase)] and excise erroneous mutagenic nucleotides inserted by nsp12. Strikingly, ribavirin can be excised from the viral genome, thus showing no antiviral activity. The crystal structure of nsp14 shows that it is unique, having been replaced by other MTase types during evolution. This unprecedented RNA correction machinery has allowed RNA genome size expansion, but also provided potential nucleoside drug resistance to these deadly pathogens.</p></abstract><abstract><p>Coronaviruses (CoVs) stand out among RNA viruses because of their unusually large genomes (∼30 kb) associated with low mutation rates. CoVs code for nsp14, a bifunctional enzyme carrying RNA cap guanine N7-methyltransferase (MTase) and 3′-5′ exoribonuclease (ExoN) activities. ExoN excises nucleotide mismatches at the RNA 3′-end in vitro, and its inactivation in vivo jeopardizes viral genetic stability. Here, we demonstrate for severe acute respiratory syndrome (SARS)-CoV an RNA synthesis and proofreading pathway through association of nsp14 with the low-fidelity nsp12 viral RNA polymerase. Through this pathway, the antiviral compound ribavirin 5′-monophosphate is significantly incorporated but also readily excised from RNA, which may explain its limited efficacy in vivo. The crystal structure at 3.38 Å resolution of SARS-CoV nsp14 in complex with its cofactor nsp10 adds to the uniqueness of CoVs among RNA viruses: The MTase domain presents a new fold that differs sharply from the canonical Rossmann fold.</p></abstract><kwd-group><kwd>RNA virus</kwd><kwd>virus replication</kwd><kwd>proofreading</kwd><kwd>ribavirin</kwd><kwd>fold evolution</kwd></kwd-group><funding-group><award-group id="gs1"><funding-source id="sp1">EC | FP7 | FP7 People: Marie-Curie Actions (PEOPLE)<named-content content-type="funder-id">100011264</named-content></funding-source><award-id rid="sp1">264286</award-id></award-group><award-group id="gs2"><funding-source id="sp2">EC | FP7 | FP7 People: Marie-Curie Actions (PEOPLE)<named-content content-type="funder-id">100011264</named-content></funding-source><award-id rid="sp2">642434</award-id></award-group><award-group id="gs3"><funding-source id="sp3">MCTI | Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)<named-content content-type="funder-id">501100003593</named-content></funding-source><award-id rid="sp3">248480/2013-8</award-id></award-group><award-group id="gs4"><funding-source id="sp4">EC | Horizon 2020 (EU Framework Programme for Research and Innovation)<named-content content-type="funder-id">501100007601</named-content></funding-source><award-id rid="sp4">260644</award-id></award-group><award-group id="gs5"><funding-source id="sp5">EC | Horizon 2020 (EU Framework Programme for Research and Innovation)<named-content content-type="funder-id">501100007601</named-content></funding-source><award-id rid="sp5">260644</award-id></award-group></funding-group><counts><page-count count="10"></page-count></counts><custom-meta-group><custom-meta><meta-name>access-type</meta-name><meta-value>free</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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