Structural Definition of a Unique Neutralization Epitope on the Receptor-Binding Domain of MERS-CoV Spike Glycoprotein
Identifieur interne : 000800 ( Main/Exploration ); précédent : 000799; suivant : 000801Structural Definition of a Unique Neutralization Epitope on the Receptor-Binding Domain of MERS-CoV Spike Glycoprotein
Auteurs : Senyan Zhang [République populaire de Chine] ; Panpan Zhou [République populaire de Chine] ; Pengfei Wang [République populaire de Chine] ; Yangyang Li [République populaire de Chine] ; Liwei Jiang [République populaire de Chine] ; Wenxu Jia [République populaire de Chine] ; Han Wang [République populaire de Chine] ; Angela Fan [République populaire de Chine] ; Dongli Wang [République populaire de Chine] ; Xuanling Shi [République populaire de Chine] ; Xianyang Fang [République populaire de Chine] ; Michal Hammel [États-Unis] ; Shuying Wang [Taïwan] ; Xinquan Wang [République populaire de Chine] ; Linqi Zhang [République populaire de Chine]Source :
- Cell Reports [ 2211-1247 ] ; 2018.
Descripteurs français
- KwdFr :
- Anticorps neutralisants (métabolisme), Coronavirus du syndrome respiratoire du Moyen-Orient (), Coronavirus du syndrome respiratoire du Moyen-Orient (génétique), Domaines protéiques, Glycoprotéine de spicule des coronavirus (), Humains, Liaison aux protéines, Modèles moléculaires, Multimérisation de protéines, Mutation (génétique), Sites de fixation, Épitopes ().
- MESH :
- génétique : Coronavirus du syndrome respiratoire du Moyen-Orient, Mutation.
- métabolisme : Anticorps neutralisants.
- Coronavirus du syndrome respiratoire du Moyen-Orient, Domaines protéiques, Glycoprotéine de spicule des coronavirus, Humains, Liaison aux protéines, Modèles moléculaires, Multimérisation de protéines, Sites de fixation, Épitopes.
English descriptors
- KwdEn :
- Antibodies, Neutralizing (metabolism), Binding Sites, Epitopes (chemistry), Humans, Middle East Respiratory Syndrome Coronavirus (chemistry), Middle East Respiratory Syndrome Coronavirus (genetics), Models, Molecular, Mutation (genetics), Protein Binding, Protein Domains, Protein Multimerization, Spike Glycoprotein, Coronavirus (chemistry).
- MESH :
- chemical , chemistry : Epitopes, Spike Glycoprotein, Coronavirus.
- chemical , metabolism : Antibodies, Neutralizing.
- chemistry : Middle East Respiratory Syndrome Coronavirus.
- genetics : Middle East Respiratory Syndrome Coronavirus, Mutation.
- Binding Sites, Humans, Models, Molecular, Protein Binding, Protein Domains, Protein Multimerization.
Abstract
The major mechanism of antibody-mediated neutralization of the Middle East respiratory syndrome coronavirus (MERS-CoV) involves competition with the cellular receptor dipeptidyl peptidase 4 (DPP4) for binding to the receptor-binding domain (RBD) of the spike (S) glycoprotein. Here, we report a unique epitope and unusual neutralizing mechanism of the isolated human antibody MERS-4. Structurally, MERS-4 approached the RBD from the outside of the RBD-DPP4 binding interface. Such binding resulted in the folding of the β5-β6 loop toward a shallow groove on the RBD interface critical for accommodating DPP4. The key residues for binding are identified through site-directed mutagenesis. Structural modeling revealed that MERS-4 binds to RBD only in the “up” position in the S trimer. Furthermore, MERS-4 demonstrated synergy with several reported antibodies. These results indicate that MERS-4 neutralizes MERS-CoV by indirect rather than direct competition with DPP4. This mechanism provides a valuable addition for the combined use of antibodies against MERS-CoV infection.
Url:
DOI: 10.1016/j.celrep.2018.06.041
PubMed: 29996104
PubMed Central: 7104183
Affiliations:
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Pengfei" uniqKey="Wang P" first="Pengfei" last="Wang">Pengfei Wang</name><affiliation wicri:level="1"><nlm:aff id="aff1">The Ministry of Education Key Laboratory of Protein Science, Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Biotherapy, School of Life Sciences, Tsinghua University, Beijing 100084, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>The Ministry of Education Key Laboratory of Protein Science, Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Biotherapy, School of Life Sciences, Tsinghua University, Beijing 100084</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Li, Yangyang" sort="Li, Yangyang" uniqKey="Li Y" first="Yangyang" last="Li">Yangyang Li</name><affiliation wicri:level="1"><nlm:aff id="aff2">Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Jiang, Liwei" sort="Jiang, Liwei" uniqKey="Jiang L" first="Liwei" last="Jiang">Liwei Jiang</name><affiliation wicri:level="1"><nlm:aff id="aff2">Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Jia, Wenxu" sort="Jia, Wenxu" uniqKey="Jia W" first="Wenxu" last="Jia">Wenxu Jia</name><affiliation wicri:level="1"><nlm:aff id="aff2">Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Wang, Han" sort="Wang, Han" uniqKey="Wang H" first="Han" last="Wang">Han Wang</name><affiliation wicri:level="1"><nlm:aff id="aff2">Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Fan, Angela" sort="Fan, Angela" uniqKey="Fan A" first="Angela" last="Fan">Angela Fan</name><affiliation wicri:level="1"><nlm:aff id="aff2">Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Wang, Dongli" sort="Wang, Dongli" uniqKey="Wang D" first="Dongli" last="Wang">Dongli Wang</name><affiliation wicri:level="1"><nlm:aff id="aff1">The Ministry of Education Key Laboratory of Protein Science, Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Biotherapy, School of Life Sciences, Tsinghua University, Beijing 100084, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>The Ministry of Education Key Laboratory of Protein Science, Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Biotherapy, School of Life Sciences, Tsinghua University, Beijing 100084</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Shi, Xuanling" sort="Shi, Xuanling" uniqKey="Shi X" first="Xuanling" last="Shi">Xuanling Shi</name><affiliation wicri:level="1"><nlm:aff id="aff2">Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Fang, Xianyang" sort="Fang, Xianyang" uniqKey="Fang X" first="Xianyang" last="Fang">Xianyang Fang</name><affiliation wicri:level="1"><nlm:aff id="aff1">The Ministry of Education Key Laboratory of Protein Science, Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Biotherapy, School of Life Sciences, Tsinghua University, Beijing 100084, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>The Ministry of Education Key Laboratory of Protein Science, Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Biotherapy, School of Life Sciences, Tsinghua University, Beijing 100084</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Hammel, Michal" sort="Hammel, Michal" uniqKey="Hammel M" first="Michal" last="Hammel">Michal Hammel</name><affiliation wicri:level="2"><nlm:aff id="aff3">Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Wang, Shuying" sort="Wang, Shuying" uniqKey="Wang S" first="Shuying" last="Wang">Shuying Wang</name><affiliation wicri:level="1"><nlm:aff id="aff4">Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan 701, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan 701</wicri:regionArea><wicri:noRegion>Tainan 701</wicri:noRegion></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">The Ministry of Education Key Laboratory of Protein Science, Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Biotherapy, School of Life Sciences, Tsinghua University, Beijing 100084, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>The Ministry of Education Key Laboratory of Protein Science, Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Biotherapy, School of Life Sciences, Tsinghua University, Beijing 100084</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="aff5">Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu</wicri:regionArea><wicri:noRegion>Chengdu</wicri:noRegion></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="aff2">Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author></analytic><series><title level="j">Cell Reports</title><idno type="eISSN">2211-1247</idno><imprint><date when="2018">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antibodies, Neutralizing (metabolism)</term><term>Binding Sites</term><term>Epitopes (chemistry)</term><term>Humans</term><term>Middle East Respiratory Syndrome Coronavirus (chemistry)</term><term>Middle East Respiratory Syndrome Coronavirus (genetics)</term><term>Models, Molecular</term><term>Mutation (genetics)</term><term>Protein Binding</term><term>Protein Domains</term><term>Protein Multimerization</term><term>Spike Glycoprotein, Coronavirus (chemistry)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Anticorps neutralisants (métabolisme)</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient ()</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient (génétique)</term><term>Domaines protéiques</term><term>Glycoprotéine de spicule des coronavirus ()</term><term>Humains</term><term>Liaison aux protéines</term><term>Modèles moléculaires</term><term>Multimérisation de protéines</term><term>Mutation (génétique)</term><term>Sites de fixation</term><term>Épitopes ()</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Epitopes</term><term>Spike Glycoprotein, Coronavirus</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Antibodies, Neutralizing</term></keywords><keywords scheme="MESH" qualifier="chemistry" xml:lang="en"><term>Middle East Respiratory Syndrome Coronavirus</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Middle East Respiratory Syndrome Coronavirus</term><term>Mutation</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term><term>Mutation</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Anticorps neutralisants</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Binding Sites</term><term>Humans</term><term>Models, Molecular</term><term>Protein Binding</term><term>Protein Domains</term><term>Protein Multimerization</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term><term>Domaines protéiques</term><term>Glycoprotéine de spicule des coronavirus</term><term>Humains</term><term>Liaison aux protéines</term><term>Modèles moléculaires</term><term>Multimérisation de protéines</term><term>Sites de fixation</term><term>Épitopes</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Summary</title><p>The major mechanism of antibody-mediated neutralization of the Middle East respiratory syndrome coronavirus (MERS-CoV) involves competition with the cellular receptor dipeptidyl peptidase 4 (DPP4) for binding to the receptor-binding domain (RBD) of the spike (S) glycoprotein. Here, we report a unique epitope and unusual neutralizing mechanism of the isolated human antibody MERS-4. Structurally, MERS-4 approached the RBD from the outside of the RBD-DPP4 binding interface. Such binding resulted in the folding of the β5-β6 loop toward a shallow groove on the RBD interface critical for accommodating DPP4. The key residues for binding are identified through site-directed mutagenesis. Structural modeling revealed that MERS-4 binds to RBD only in the “up” position in the S trimer. Furthermore, MERS-4 demonstrated synergy with several reported antibodies. These results indicate that MERS-4 neutralizes MERS-CoV by indirect rather than direct competition with DPP4. This mechanism provides a valuable addition for the combined use of antibodies against MERS-CoV infection.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Adams, P D" uniqKey="Adams P">P.D. 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