Structural definition of a neutralization epitope on the N-terminal domain of MERS-CoV spike glycoprotein
Identifieur interne : 000408 ( Pmc/Curation ); précédent : 000407; suivant : 000409Structural definition of a neutralization epitope on the N-terminal domain of MERS-CoV spike glycoprotein
Auteurs : Haixia Zhou [République populaire de Chine] ; Yingzhu Chen [République populaire de Chine] ; Shuyuan Zhang [République populaire de Chine] ; Peihua Niu [République populaire de Chine] ; Kun Qin [République populaire de Chine] ; Wenxu Jia [République populaire de Chine] ; Baoying Huang [République populaire de Chine] ; Senyan Zhang [République populaire de Chine] ; Jun Lan [République populaire de Chine] ; Linqi Zhang [République populaire de Chine] ; Wenjie Tan [République populaire de Chine] ; Xinquan Wang [République populaire de Chine]Source :
- Nature Communications [ 2041-1723 ] ; 2019.
Abstract
Most neutralizing antibodies against Middle East respiratory syndrome coronavirus (MERS-CoV) target the receptor-binding domain (RBD) of the spike glycoprotein and block its binding to the cellular receptor dipeptidyl peptidase 4 (DPP4). The epitopes and mechanisms of mAbs targeting non-RBD regions have not been well characterized yet. Here we report the monoclonal antibody 7D10 that binds to the N-terminal domain (NTD) of the spike glycoprotein and inhibits the cell entry of MERS-CoV with high potency. Structure determination and mutagenesis experiments reveal the epitope and critical residues on the NTD for 7D10 binding and neutralization. Further experiments indicate that the neutralization by 7D10 is not solely dependent on the inhibition of DPP4 binding, but also acts after viral cell attachment, inhibiting the pre-fusion to post-fusion conformational change of the spike. These properties give 7D10 a wide neutralization breadth and help explain its synergistic effects with several RBD-targeting antibodies.
Url:
DOI: 10.1038/s41467-019-10897-4
PubMed: 31296843
PubMed Central: 6624210
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Planning Commission, National Institute for Viral Disease Control and Prevention, China CDC, 102206 Beijing</wicri:regionArea></affiliation></author><author><name sortKey="Zhang, Senyan" sort="Zhang, Senyan" uniqKey="Zhang S" first="Senyan" last="Zhang">Senyan Zhang</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0662 3178</institution-id><institution-id institution-id-type="GRID">grid.12527.33</institution-id><institution>The Ministry of Education Key Laboratory of Protein Science, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Collaborative Innovation Center for Biotherapy, School of Life Sciences,</institution><institution>Tsinghua University,</institution></institution-wrap>100084 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>100084 Beijing</wicri:regionArea></affiliation></author><author><name sortKey="Lan, Jun" sort="Lan, Jun" uniqKey="Lan J" first="Jun" last="Lan">Jun Lan</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0662 3178</institution-id><institution-id institution-id-type="GRID">grid.12527.33</institution-id><institution>The Ministry of Education Key Laboratory of Protein Science, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Collaborative Innovation Center for Biotherapy, School of Life Sciences,</institution><institution>Tsinghua University,</institution></institution-wrap>100084 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>100084 Beijing</wicri:regionArea></affiliation></author><author><name sortKey="Zhang, Linqi" sort="Zhang, Linqi" uniqKey="Zhang L" first="Linqi" last="Zhang">Linqi Zhang</name><affiliation wicri:level="1"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0662 3178</institution-id><institution-id institution-id-type="GRID">grid.12527.33</institution-id><institution>Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Basic Medical Sciences, School of Medicine,</institution><institution> Tsinghua University,</institution></institution-wrap>100084 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>100084 Beijing</wicri:regionArea></affiliation></author><author><name sortKey="Tan, Wenjie" sort="Tan, Wenjie" uniqKey="Tan W" first="Wenjie" last="Tan">Wenjie Tan</name><affiliation wicri:level="1"><nlm:aff id="Aff2">Key Laboratory of Medical Virology, National Health and Family Planning Commission, National Institute for Viral Disease Control and Prevention, China CDC, 102206 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Key Laboratory of Medical Virology, National Health and Family Planning Commission, National Institute for Viral Disease Control and Prevention, China CDC, 102206 Beijing</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Xinquan" sort="Wang, Xinquan" uniqKey="Wang X" first="Xinquan" last="Wang">Xinquan Wang</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0662 3178</institution-id><institution-id institution-id-type="GRID">grid.12527.33</institution-id><institution>The Ministry of Education Key Laboratory of Protein Science, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Collaborative Innovation Center for Biotherapy, School of Life Sciences,</institution><institution>Tsinghua University,</institution></institution-wrap>100084 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>100084 Beijing</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0807 1581</institution-id><institution-id institution-id-type="GRID">grid.13291.38</institution-id><institution>Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School,</institution><institution>Sichuan University,</institution></institution-wrap>610065 Chengdu, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>610065 Chengdu</wicri:regionArea></affiliation></author></analytic><series><title level="j">Nature Communications</title><idno type="eISSN">2041-1723</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="Par1">Most neutralizing antibodies against Middle East respiratory syndrome coronavirus (MERS-CoV) target the receptor-binding domain (RBD) of the spike glycoprotein and block its binding to the cellular receptor dipeptidyl peptidase 4 (DPP4). The epitopes and mechanisms of mAbs targeting non-RBD regions have not been well characterized yet. Here we report the monoclonal antibody 7D10 that binds to the N-terminal domain (NTD) of the spike glycoprotein and inhibits the cell entry of MERS-CoV with high potency. Structure determination and mutagenesis experiments reveal the epitope and critical residues on the NTD for 7D10 binding and neutralization. Further experiments indicate that the neutralization by 7D10 is not solely dependent on the inhibition of DPP4 binding, but also acts after viral cell attachment, inhibiting the pre-fusion to post-fusion conformational change of the spike. These properties give 7D10 a wide neutralization breadth and help explain its synergistic effects with several RBD-targeting antibodies.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Zaki, Am" uniqKey="Zaki A">AM Zaki</name></author><author><name sortKey="Van Boheemen, S" uniqKey="Van Boheemen S">S van Boheemen</name></author><author><name sortKey="Bestebroer, Tm" uniqKey="Bestebroer T">TM Bestebroer</name></author><author><name sortKey="Osterhaus, Ad" uniqKey="Osterhaus A">AD Osterhaus</name></author><author><name sortKey="Fouchier, Ra" uniqKey="Fouchier R">RA Fouchier</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chan, Jf" uniqKey="Chan J">JF Chan</name></author><author><name sortKey="Lau, Sk" uniqKey="Lau S">SK Lau</name></author><author><name sortKey="Woo, Pc" uniqKey="Woo P">PC Woo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Haagmans, Bl" 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Nat Commun</journal-id><journal-id journal-id-type="iso-abbrev">Nat Commun</journal-id><journal-title-group><journal-title>Nature Communications</journal-title></journal-title-group><issn pub-type="epub">2041-1723</issn><publisher><publisher-name>Nature Publishing Group UK</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31296843</article-id><article-id pub-id-type="pmc">6624210</article-id><article-id pub-id-type="publisher-id">10897</article-id><article-id pub-id-type="doi">10.1038/s41467-019-10897-4</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Structural definition of a neutralization epitope on the N-terminal domain of MERS-CoV spike glycoprotein</article-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-9676-6267</contrib-id><name><surname>Zhou</surname><given-names>Haixia</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Chen</surname><given-names>Yingzhu</given-names></name><xref ref-type="aff" rid="Aff2">2</xref><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Shuyuan</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Niu</surname><given-names>Peihua</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Qin</surname><given-names>Kun</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Jia</surname><given-names>Wenxu</given-names></name><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Huang</surname><given-names>Baoying</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Senyan</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Lan</surname><given-names>Jun</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Linqi</given-names></name><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Tan</surname><given-names>Wenjie</given-names></name><address><email>tanwj28@163.com</email></address><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Wang</surname><given-names>Xinquan</given-names></name><address><email>xinquanwang@mail.tsinghua.edu.cn</email></address><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff5">5</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0662 3178</institution-id><institution-id institution-id-type="GRID">grid.12527.33</institution-id><institution>The Ministry of Education Key Laboratory of Protein Science, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Collaborative Innovation Center for Biotherapy, School of Life Sciences,</institution><institution>Tsinghua University,</institution></institution-wrap>100084 Beijing, China</aff><aff id="Aff2"><label>2</label>Key Laboratory of Medical Virology, National Health and Family Planning Commission, National Institute for Viral Disease Control and Prevention, China CDC, 102206 Beijing, China</aff><aff id="Aff3"><label>3</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0027 0586</institution-id><institution-id institution-id-type="GRID">grid.412474.0</institution-id><institution>Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Clinical Laboratory,</institution><institution>Peking University Cancer Hospital & Institute,</institution></institution-wrap>100142 Beijing, China</aff><aff id="Aff4"><label>4</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0662 3178</institution-id><institution-id institution-id-type="GRID">grid.12527.33</institution-id><institution>Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Basic Medical Sciences, School of Medicine,</institution><institution> Tsinghua University,</institution></institution-wrap>100084 Beijing, China</aff><aff id="Aff5"><label>5</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0807 1581</institution-id><institution-id institution-id-type="GRID">grid.13291.38</institution-id><institution>Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School,</institution><institution>Sichuan University,</institution></institution-wrap>610065 Chengdu, China</aff></contrib-group><pub-date pub-type="epub"><day>11</day><month>7</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>11</day><month>7</month><year>2019</year></pub-date><pub-date pub-type="collection"><year>2019</year></pub-date><volume>10</volume><elocation-id>3068</elocation-id><history><date date-type="received"><day>10</day><month>12</month><year>2018</year></date><date date-type="accepted"><day>5</day><month>6</month><year>2019</year></date></history><permissions><copyright-statement>© The Author(s) 2019</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold> This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>.</license-p></license></permissions><abstract id="Abs1"><p id="Par1">Most neutralizing antibodies against Middle East respiratory syndrome coronavirus (MERS-CoV) target the receptor-binding domain (RBD) of the spike glycoprotein and block its binding to the cellular receptor dipeptidyl peptidase 4 (DPP4). The epitopes and mechanisms of mAbs targeting non-RBD regions have not been well characterized yet. Here we report the monoclonal antibody 7D10 that binds to the N-terminal domain (NTD) of the spike glycoprotein and inhibits the cell entry of MERS-CoV with high potency. Structure determination and mutagenesis experiments reveal the epitope and critical residues on the NTD for 7D10 binding and neutralization. Further experiments indicate that the neutralization by 7D10 is not solely dependent on the inhibition of DPP4 binding, but also acts after viral cell attachment, inhibiting the pre-fusion to post-fusion conformational change of the spike. These properties give 7D10 a wide neutralization breadth and help explain its synergistic effects with several RBD-targeting antibodies.</p></abstract><abstract id="Abs2" abstract-type="web-summary"><p id="Par2">Antibodies that target the N-terminal domain (NTD) of the MERS-CoV spike remain poorly characterized. Here, Zhou et al. report the structural and functional analysis of the NTD-targeting mAb 7D10 and show that it synergizes with antibodies targeting the receptor-binding domain against different MERS-CoV strains.</p></abstract><kwd-group kwd-group-type="npg-subject"><title>Subject terms</title><kwd>Virology</kwd><kwd>Virology</kwd><kwd>X-ray crystallography</kwd><kwd>X-ray crystallography</kwd></kwd-group><funding-group><award-group><funding-source><institution>the National Key Plan for Scientific Research and Development of China (grants 2016YFD0500301), the National Major Project for Control and Prevention of Infectious Disease in China (2016ZX10004001-003).</institution></funding-source></award-group></funding-group><funding-group><award-group><funding-source><institution>the National Key Plan for Scientific Research and Development of China (grants 2016YFD0500307), the National Natural Science Foundation of China (grants 31470751 and U1405228).</institution></funding-source></award-group></funding-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2019</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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