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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Structural and Biochemical Characterization of Endoribonuclease Nsp15 Encoded by Middle East Respiratory Syndrome Coronavirus</title><author><name sortKey="Zhang, Lianqi" sort="Zhang, Lianqi" uniqKey="Zhang L" first="Lianqi" last="Zhang">Lianqi Zhang</name><affiliation><nlm:aff id="aff1">Laboratory of Structural Biology, School of Medicine, Tsinghua University, Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Li, Lei" sort="Li, Lei" uniqKey="Li L" first="Lei" last="Li">Lei Li</name><affiliation><nlm:aff id="aff2">State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China</nlm:aff></affiliation></author><author><name sortKey="Yan, Liming" sort="Yan, Liming" uniqKey="Yan L" first="Liming" last="Yan">Liming Yan</name><affiliation><nlm:aff id="aff1">Laboratory of Structural Biology, School of Medicine, Tsinghua University, Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Ming, Zhenhua" sort="Ming, Zhenhua" uniqKey="Ming Z" first="Zhenhua" last="Ming">Zhenhua Ming</name><affiliation><nlm:aff id="aff3">State Key Laboratory of Conservation and Utilization of Subtropical Agro-Bioresources, College of Life Science and Technology, Guangxi University, Nanning, China</nlm:aff></affiliation></author><author><name sortKey="Jia, Zhihui" sort="Jia, Zhihui" uniqKey="Jia Z" first="Zhihui" last="Jia">Zhihui Jia</name><affiliation><nlm:aff id="aff1">Laboratory of Structural Biology, School of Medicine, Tsinghua University, Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Lou, Zhiyong" sort="Lou, Zhiyong" uniqKey="Lou Z" first="Zhiyong" last="Lou">Zhiyong Lou</name><affiliation><nlm:aff id="aff1">Laboratory of Structural Biology, School of Medicine, Tsinghua University, Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Rao, Zihe" sort="Rao, Zihe" uniqKey="Rao Z" first="Zihe" last="Rao">Zihe Rao</name><affiliation><nlm:aff id="aff1">Laboratory of Structural Biology, School of Medicine, Tsinghua University, Beijing, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">College of Life Sciences, Nankai University, Tianjin, China</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">30135128</idno><idno type="pmc">6206473</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206473</idno><idno type="RBID">PMC:6206473</idno><idno type="doi">10.1128/JVI.00893-18</idno><date when="2018">2018</date><idno type="wicri:Area/Pmc/Corpus">000C94</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000C94</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Structural and Biochemical Characterization of Endoribonuclease Nsp15 Encoded by Middle East Respiratory Syndrome Coronavirus</title><author><name sortKey="Zhang, Lianqi" sort="Zhang, Lianqi" uniqKey="Zhang L" first="Lianqi" last="Zhang">Lianqi Zhang</name><affiliation><nlm:aff id="aff1">Laboratory of Structural Biology, School of Medicine, Tsinghua University, Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Li, Lei" sort="Li, Lei" uniqKey="Li L" first="Lei" last="Li">Lei Li</name><affiliation><nlm:aff id="aff2">State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China</nlm:aff></affiliation></author><author><name sortKey="Yan, Liming" sort="Yan, Liming" uniqKey="Yan L" first="Liming" last="Yan">Liming Yan</name><affiliation><nlm:aff id="aff1">Laboratory of Structural Biology, School of Medicine, Tsinghua University, Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Ming, Zhenhua" sort="Ming, Zhenhua" uniqKey="Ming Z" first="Zhenhua" last="Ming">Zhenhua Ming</name><affiliation><nlm:aff id="aff3">State Key Laboratory of Conservation and Utilization of Subtropical Agro-Bioresources, College of Life Science and Technology, Guangxi University, Nanning, China</nlm:aff></affiliation></author><author><name sortKey="Jia, Zhihui" sort="Jia, Zhihui" uniqKey="Jia Z" first="Zhihui" last="Jia">Zhihui Jia</name><affiliation><nlm:aff id="aff1">Laboratory of Structural Biology, School of Medicine, Tsinghua University, Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Lou, Zhiyong" sort="Lou, Zhiyong" uniqKey="Lou Z" first="Zhiyong" last="Lou">Zhiyong Lou</name><affiliation><nlm:aff id="aff1">Laboratory of Structural Biology, School of Medicine, Tsinghua University, Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Rao, Zihe" sort="Rao, Zihe" uniqKey="Rao Z" first="Zihe" last="Rao">Zihe Rao</name><affiliation><nlm:aff id="aff1">Laboratory of Structural Biology, School of Medicine, Tsinghua University, Beijing, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">College of Life Sciences, Nankai University, Tianjin, China</nlm:aff></affiliation></author></analytic><series><title level="j">Journal of Virology</title><idno type="ISSN">0022-538X</idno><idno type="eISSN">1098-5514</idno><imprint><date when="2018">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The lethally pathogenic Middle East respiratory syndrome coronavirus (MERS-CoV) and the severe acute respiratory syndrome coronavirus (SARS-CoV) pose serious threats to humans. Endoribonuclease Nsp15 encoded by coronavirus plays an important role in viral infection and pathogenesis. This study determines the structure of MERS-CoV Nsp15 and demonstrates how the catalytic activity of this protein is potentially mediated, thereby providing structural and functional evidence for developing antiviral drugs. We also hypothesize that the primase-like protein Nsp8 and the Nsp7/Nsp8 complex may interact with Nsp15 and affect enzymatic activity. This contributes to the understanding of the association of Nsp15 with the viral replication and transcription machinery.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Virol</journal-id><journal-id journal-id-type="iso-abbrev">J. Virol</journal-id><journal-id journal-id-type="hwp">jvi</journal-id><journal-id journal-id-type="pmc">jvi</journal-id><journal-id journal-id-type="publisher-id">JVI</journal-id><journal-title-group><journal-title>Journal of Virology</journal-title></journal-title-group><issn pub-type="ppub">0022-538X</issn><issn pub-type="epub">1098-5514</issn><publisher><publisher-name>American Society for Microbiology</publisher-name><publisher-loc>1752 N St., N.W., Washington, DC</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">30135128</article-id><article-id pub-id-type="pmc">6206473</article-id><article-id pub-id-type="publisher-id">00893-18</article-id><article-id pub-id-type="doi">10.1128/JVI.00893-18</article-id><article-categories><subj-group subj-group-type="heading"><subject>Structure and Assembly</subject></subj-group></article-categories><title-group><article-title>Structural and Biochemical Characterization of Endoribonuclease Nsp15 Encoded by Middle East Respiratory Syndrome Coronavirus</article-title><alt-title alt-title-type="running-head">Crystal Structure of MERS-CoV Nsp15</alt-title><alt-title alt-title-type="short-authors">Zhang et al.</alt-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Zhang</surname><given-names>Lianqi</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Li</surname><given-names>Lei</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author" equal-contrib="no"><name><surname>Yan</surname><given-names>Liming</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author" equal-contrib="no"><name><surname>Ming</surname><given-names>Zhenhua</given-names></name><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author" equal-contrib="no"><name><surname>Jia</surname><given-names>Zhihui</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author" equal-contrib="no"><name><surname>Lou</surname><given-names>Zhiyong</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author" corresp="yes" equal-contrib="no"><name><surname>Rao</surname><given-names>Zihe</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff4"><sup>d</sup></xref><xref ref-type="aff" rid="aff5"><sup>e</sup></xref></contrib><aff id="aff1"><label>a</label>Laboratory of Structural Biology, School of Medicine, Tsinghua University, Beijing, China</aff><aff id="aff2"><label>b</label>State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China</aff><aff id="aff3"><label>c</label>State Key Laboratory of Conservation and Utilization of Subtropical Agro-Bioresources, College of Life Science and Technology, Guangxi University, Nanning, China</aff><aff id="aff4"><label>d</label>National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, China</aff><aff id="aff5"><label>e</label>College of Life Sciences, Nankai University, Tianjin, China</aff></contrib-group><contrib-group><contrib contrib-type="editor"><name><surname>Gallagher</surname><given-names>Tom</given-names></name><role>Editor</role><aff>Loyola University Medical Center</aff></contrib></contrib-group><author-notes><corresp id="cor1">Address correspondence to Zihe Rao, <email>raozh@mail.tsinghua.edu.cn</email>.</corresp><fn fn-type="equal"><p>L.Z. and L.L. contributed equally to this article.</p></fn><fn fn-type="other"><p><bold>Citation</bold> Zhang L, Li L, Yan L, Ming Z, Jia Z, Lou Z, Rao Z. 2018. Structural and biochemical characterization of endoribonuclease Nsp15 encoded by Middle East respiratory syndrome coronavirus. J Virol 92:e00893-18. <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/JVI.00893-18">https://doi.org/10.1128/JVI.00893-18</ext-link>.</p></fn></author-notes><pub-date pub-type="epreprint"><day>22</day><month>8</month><year>2018</year></pub-date><pub-date pub-type="epub"><day>29</day><month>10</month><year>2018</year></pub-date><pub-date pub-type="collection"><day>15</day><month>11</month><year>2018</year></pub-date><volume>92</volume><issue>22</issue><elocation-id>e00893-18</elocation-id><history><date date-type="received"><day>21</day><month>5</month><year>2018</year></date><date date-type="accepted"><day>2</day><month>8</month><year>2018</year></date></history><permissions><copyright-statement>Copyright © 2018 American Society for Microbiology.</copyright-statement><copyright-year>2018</copyright-year><copyright-holder>American Society for Microbiology</copyright-holder><license license-type="asm" xlink:href="https://doi.org/10.1128/ASMCopyrightv2"><license-p><ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/ASMCopyrightv2">All Rights Reserved</ext-link>.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="zjv022183980001.pdf"></self-uri><abstract abstract-type="precis"><p>The lethally pathogenic Middle East respiratory syndrome coronavirus (MERS-CoV) and the severe acute respiratory syndrome coronavirus (SARS-CoV) pose serious threats to humans. Endoribonuclease Nsp15 encoded by coronavirus plays an important role in viral infection and pathogenesis. This study determines the structure of MERS-CoV Nsp15 and demonstrates how the catalytic activity of this protein is potentially mediated, thereby providing structural and functional evidence for developing antiviral drugs. We also hypothesize that the primase-like protein Nsp8 and the Nsp7/Nsp8 complex may interact with Nsp15 and affect enzymatic activity. This contributes to the understanding of the association of Nsp15 with the viral replication and transcription machinery.</p></abstract><abstract><title>ABSTRACT</title><p>Nonstructural protein 15 (Nsp15) encoded by coronavirus (CoV) is a nidoviral uridylate-specific endoribonuclease (NendoU) that plays an essential role in the life cycle of the virus. Structural information on this crucial protein from the Middle East respiratory syndrome CoV (MERS-CoV), which is lethally pathogenic and has caused severe respiratory diseases worldwide, is lacking. Here, we determined the crystal structure of MERS-CoV Nsp15 at a 2.7-Å resolution and performed the relevant biochemical assays to study how NendoU activity is regulated. Although the overall structure is conserved, MERS-CoV Nsp15 shows unique and novel features compared to its homologs. Serine substitution of residue F285, which harbors an aromatic side chain that disturbs RNA binding compared with that of other homologs, increases catalytic activity. Mutations of residues residing on the oligomerization interfaces that distort hexamerization, namely, N38A, Y58A, and N157A, decrease thermostability, decrease affinity of binding with RNA, and reduce the NendoU activity of Nsp15. In contrast, mutant D39A exhibits increased activity and a higher substrate binding capacity. Importantly, Nsp8 was found to interact with both monomeric and hexameric Nsp15. The Nsp7/Nsp8 complex displays a higher binding affinity for Nsp15. Furthermore, Nsp8 and the Nsp7/Nsp8 complex also enhance the NendoU activity of hexameric Nsp15 <italic>in vitro</italic>. Taking the findings together, this work first provides evidence on how the activity of Nsp15 may be functionally mediated by catalytic residues, oligomeric assembly, RNA binding efficiency, or the possible association with other nonstructural proteins.</p><p><bold>IMPORTANCE</bold> The lethally pathogenic Middle East respiratory syndrome coronavirus (MERS-CoV) and the severe acute respiratory syndrome coronavirus (SARS-CoV) pose serious threats to humans. Endoribonuclease Nsp15 encoded by coronavirus plays an important role in viral infection and pathogenesis. This study determines the structure of MERS-CoV Nsp15 and demonstrates how the catalytic activity of this protein is potentially mediated, thereby providing structural and functional evidence for developing antiviral drugs. We also hypothesize that the primase-like protein Nsp8 and the Nsp7/Nsp8 complex may interact with Nsp15 and affect enzymatic activity. This contributes to the understanding of the association of Nsp15 with the viral replication and transcription machinery.</p></abstract><kwd-group><title>KEYWORDS</title><kwd>MERS-CoV</kwd><kwd>endoribonuclease</kwd><kwd>crystal structure</kwd><kwd>oligomerization</kwd></kwd-group><funding-group><award-group id="award1"><funding-source id="gs1"><institution-wrap><institution>National Natural Science Foundation of China (NSFC)</institution><institution-id>https://doi.org/10.13039/501100001809</institution-id></institution-wrap></funding-source><award-id rid="gs1">81330036</award-id><award-id rid="gs1">31570717</award-id><award-id rid="gs1">81621005</award-id><award-id rid="gs1">81520108019</award-id><principal-award-recipient><name><surname>Rao</surname><given-names>Zihe</given-names></name></principal-award-recipient></award-group><award-group id="award2"><funding-source id="gs2"><institution-wrap><institution>Ministry of Science and Technology of the People's Republic of China (MOST)</institution><institution-id>https://doi.org/10.13039/501100002855</institution-id></institution-wrap></funding-source><award-id rid="gs2">2017YFC0840300</award-id><principal-award-recipient><name><surname>Rao</surname><given-names>Zihe</given-names></name></principal-award-recipient></award-group></funding-group><counts><fig-count count="8"></fig-count><table-count count="3"></table-count><equation-count count="0"></equation-count><ref-count count="31"></ref-count><page-count count="16"></page-count><word-count count="8801"></word-count></counts><custom-meta-group><custom-meta><meta-name>cover-date</meta-name><meta-value>November 2018</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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