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Neutralization of SARS-CoV-2 by Destruction of the Prefusion Spike.

Identifieur interne : 000017 ( Main/Exploration ); précédent : 000016; suivant : 000018

Neutralization of SARS-CoV-2 by Destruction of the Prefusion Spike.

Auteurs : Jiandong Huo [Royaume-Uni] ; Yuguang Zhao [Royaume-Uni] ; Jingshan Ren [Royaume-Uni] ; Daming Zhou [Royaume-Uni] ; Helen M E. Duyvesteyn [Royaume-Uni] ; Helen M. Ginn [Royaume-Uni] ; Loic Carrique [Royaume-Uni] ; Tomas Malinauskas [Royaume-Uni] ; Reinis R. Ruza [Royaume-Uni] ; Pranav N M. Shah [Royaume-Uni] ; Tiong Kit Tan [Royaume-Uni] ; Pramila Rijal [Royaume-Uni] ; Naomi Coombes [Royaume-Uni] ; Kevin R. Bewley [Royaume-Uni] ; Julia A. Tree [Royaume-Uni] ; Julika Radecke [Royaume-Uni] ; Neil G. Paterson [Royaume-Uni] ; Piyada Supasa [Royaume-Uni] ; Juthathip Mongkolsapaya [Thaïlande] ; Gavin R. Screaton [Royaume-Uni] ; Miles Carroll [Royaume-Uni] ; Alain Townsend [Royaume-Uni] ; Elizabeth E. Fry [Royaume-Uni] ; Raymond J. Owens [Royaume-Uni] ; David I. Stuart [Royaume-Uni]

Source :

RBID : pubmed:32585135

Descripteurs français

English descriptors

Abstract

There are as yet no licensed therapeutics for the COVID-19 pandemic. The causal coronavirus (SARS-CoV-2) binds host cells via a trimeric spike whose receptor binding domain (RBD) recognizes angiotensin-converting enzyme 2, initiating conformational changes that drive membrane fusion. We find that the monoclonal antibody CR3022 binds the RBD tightly, neutralizing SARS-CoV-2, and report the crystal structure at 2.4 Å of the Fab/RBD complex. Some crystals are suitable for screening for entry-blocking inhibitors. The highly conserved, structure-stabilizing CR3022 epitope is inaccessible in the prefusion spike, suggesting that CR3022 binding facilitates conversion to the fusion-incompetent post-fusion state. Cryogenic electron microscopy (cryo-EM) analysis confirms that incubation of spike with CR3022 Fab leads to destruction of the prefusion trimer. Presentation of this cryptic epitope in an RBD-based vaccine might advantageously focus immune responses. Binders at this epitope could be useful therapeutically, possibly in synergy with an antibody that blocks receptor attachment.

DOI: 10.1016/j.chom.2020.06.010
PubMed: 32585135
PubMed Central: PMC7303615


Affiliations:


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<nlm:affiliation>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK; The Rosalind Franklin Institute, Harwell Campus, OX11 0FA, UK; Protein Production UK, Research Complex at Harwell, Harwell Science & Innovation Campus, Didcot, OX11 0FA, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK; The Rosalind Franklin Institute, Harwell Campus, OX11 0FA, UK; Protein Production UK, Research Complex at Harwell, Harwell Science & Innovation Campus, Didcot, OX11 0FA</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName>
<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Zhao, Yuguang" sort="Zhao, Yuguang" uniqKey="Zhao Y" first="Yuguang" last="Zhao">Yuguang Zhao</name>
<affiliation wicri:level="4">
<nlm:affiliation>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName>
<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Ren, Jingshan" sort="Ren, Jingshan" uniqKey="Ren J" first="Jingshan" last="Ren">Jingshan Ren</name>
<affiliation wicri:level="4">
<nlm:affiliation>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK. Electronic address: ren@strubi.ox.ac.uk.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName>
<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Zhou, Daming" sort="Zhou, Daming" uniqKey="Zhou D" first="Daming" last="Zhou">Daming Zhou</name>
<affiliation wicri:level="4">
<nlm:affiliation>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName>
<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Duyvesteyn, Helen M E" sort="Duyvesteyn, Helen M E" uniqKey="Duyvesteyn H" first="Helen M E" last="Duyvesteyn">Helen M E. Duyvesteyn</name>
<affiliation wicri:level="4">
<nlm:affiliation>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName>
<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Ginn, Helen M" sort="Ginn, Helen M" uniqKey="Ginn H" first="Helen M" last="Ginn">Helen M. Ginn</name>
<affiliation wicri:level="1">
<nlm:affiliation>Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot, OX11 0DE, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot, OX11 0DE</wicri:regionArea>
<wicri:noRegion>OX11 0DE</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Carrique, Loic" sort="Carrique, Loic" uniqKey="Carrique L" first="Loic" last="Carrique">Loic Carrique</name>
<affiliation wicri:level="4">
<nlm:affiliation>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName>
<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Malinauskas, Tomas" sort="Malinauskas, Tomas" uniqKey="Malinauskas T" first="Tomas" last="Malinauskas">Tomas Malinauskas</name>
<affiliation wicri:level="4">
<nlm:affiliation>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName>
<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Ruza, Reinis R" sort="Ruza, Reinis R" uniqKey="Ruza R" first="Reinis R" last="Ruza">Reinis R. Ruza</name>
<affiliation wicri:level="4">
<nlm:affiliation>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName>
<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Shah, Pranav N M" sort="Shah, Pranav N M" uniqKey="Shah P" first="Pranav N M" last="Shah">Pranav N M. Shah</name>
<affiliation wicri:level="4">
<nlm:affiliation>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName>
<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Tan, Tiong Kit" sort="Tan, Tiong Kit" uniqKey="Tan T" first="Tiong Kit" last="Tan">Tiong Kit Tan</name>
<affiliation wicri:level="4">
<nlm:affiliation>MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName>
<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Rijal, Pramila" sort="Rijal, Pramila" uniqKey="Rijal P" first="Pramila" last="Rijal">Pramila Rijal</name>
<affiliation wicri:level="4">
<nlm:affiliation>MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK; Centre for Translational Immunology, Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford OX3 7FZ, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK; Centre for Translational Immunology, Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford OX3 7FZ</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName>
<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Coombes, Naomi" sort="Coombes, Naomi" uniqKey="Coombes N" first="Naomi" last="Coombes">Naomi Coombes</name>
<affiliation wicri:level="1">
<nlm:affiliation>National Infection Service, Public Health England, Porton Down, Salisbury, SP4 0JG, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>National Infection Service, Public Health England, Porton Down, Salisbury, SP4 0JG</wicri:regionArea>
<wicri:noRegion>SP4 0JG</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Bewley, Kevin R" sort="Bewley, Kevin R" uniqKey="Bewley K" first="Kevin R" last="Bewley">Kevin R. Bewley</name>
<affiliation wicri:level="1">
<nlm:affiliation>National Infection Service, Public Health England, Porton Down, Salisbury, SP4 0JG, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>National Infection Service, Public Health England, Porton Down, Salisbury, SP4 0JG</wicri:regionArea>
<wicri:noRegion>SP4 0JG</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Tree, Julia A" sort="Tree, Julia A" uniqKey="Tree J" first="Julia A" last="Tree">Julia A. Tree</name>
<affiliation wicri:level="1">
<nlm:affiliation>National Infection Service, Public Health England, Porton Down, Salisbury, SP4 0JG, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>National Infection Service, Public Health England, Porton Down, Salisbury, SP4 0JG</wicri:regionArea>
<wicri:noRegion>SP4 0JG</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Radecke, Julika" sort="Radecke, Julika" uniqKey="Radecke J" first="Julika" last="Radecke">Julika Radecke</name>
<affiliation wicri:level="1">
<nlm:affiliation>Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot, OX11 0DE, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot, OX11 0DE</wicri:regionArea>
<wicri:noRegion>OX11 0DE</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Paterson, Neil G" sort="Paterson, Neil G" uniqKey="Paterson N" first="Neil G" last="Paterson">Neil G. Paterson</name>
<affiliation wicri:level="1">
<nlm:affiliation>Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot, OX11 0DE, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot, OX11 0DE</wicri:regionArea>
<wicri:noRegion>OX11 0DE</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Supasa, Piyada" sort="Supasa, Piyada" uniqKey="Supasa P" first="Piyada" last="Supasa">Piyada Supasa</name>
<affiliation wicri:level="4">
<nlm:affiliation>Nuffield Department of Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Nuffield Department of Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName>
<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Mongkolsapaya, Juthathip" sort="Mongkolsapaya, Juthathip" uniqKey="Mongkolsapaya J" first="Juthathip" last="Mongkolsapaya">Juthathip Mongkolsapaya</name>
<affiliation wicri:level="4">
<nlm:affiliation>Nuffield Department of Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK; Dengue Hemorrhagic Fever Research Unit, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 73170, Thailand.</nlm:affiliation>
<country xml:lang="fr">Thaïlande</country>
<wicri:regionArea>Nuffield Department of Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK; Dengue Hemorrhagic Fever Research Unit, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 73170</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName>
<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Screaton, Gavin R" sort="Screaton, Gavin R" uniqKey="Screaton G" first="Gavin R" last="Screaton">Gavin R. Screaton</name>
<affiliation wicri:level="4">
<nlm:affiliation>Nuffield Department of Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Nuffield Department of Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName>
<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Carroll, Miles" sort="Carroll, Miles" uniqKey="Carroll M" first="Miles" last="Carroll">Miles Carroll</name>
<affiliation wicri:level="4">
<nlm:affiliation>National Infection Service, Public Health England, Porton Down, Salisbury, SP4 0JG, UK; Nuffield Department of Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>National Infection Service, Public Health England, Porton Down, Salisbury, SP4 0JG, UK; Nuffield Department of Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName>
<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Townsend, Alain" sort="Townsend, Alain" uniqKey="Townsend A" first="Alain" last="Townsend">Alain Townsend</name>
<affiliation wicri:level="4">
<nlm:affiliation>MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK; Centre for Translational Immunology, Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford OX3 7FZ, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK; Centre for Translational Immunology, Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford OX3 7FZ</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName>
<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Fry, Elizabeth E" sort="Fry, Elizabeth E" uniqKey="Fry E" first="Elizabeth E" last="Fry">Elizabeth E. Fry</name>
<affiliation wicri:level="4">
<nlm:affiliation>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName>
<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Owens, Raymond J" sort="Owens, Raymond J" uniqKey="Owens R" first="Raymond J" last="Owens">Raymond J. Owens</name>
<affiliation wicri:level="4">
<nlm:affiliation>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK; The Rosalind Franklin Institute, Harwell Campus, OX11 0FA, UK; Protein Production UK, Research Complex at Harwell, Harwell Science & Innovation Campus, Didcot, OX11 0FA, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK; The Rosalind Franklin Institute, Harwell Campus, OX11 0FA, UK; Protein Production UK, Research Complex at Harwell, Harwell Science & Innovation Campus, Didcot, OX11 0FA</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName>
<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Stuart, David I" sort="Stuart, David I" uniqKey="Stuart D" first="David I" last="Stuart">David I. Stuart</name>
<affiliation wicri:level="4">
<nlm:affiliation>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK; Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot, OX11 0DE, UK; Instruct-ERIC, Oxford House, Parkway Court, John Smith Drive, Oxford, OX4 2JY, UK. Electronic address: dave@strubi.ox.ac.uk.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK; Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot, OX11 0DE, UK; Instruct-ERIC, Oxford House, Parkway Court, John Smith Drive, Oxford, OX4 2JY</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName>
<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
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<series>
<title level="j">Cell host & microbe</title>
<idno type="eISSN">1934-6069</idno>
<imprint>
<date when="2020" type="published">2020</date>
</imprint>
</series>
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<keywords scheme="KwdEn" xml:lang="en">
<term>Allosteric Site (MeSH)</term>
<term>Amino Acid Sequence (MeSH)</term>
<term>Antibodies, Monoclonal (immunology)</term>
<term>Antibodies, Neutralizing (immunology)</term>
<term>Antibodies, Neutralizing (therapeutic use)</term>
<term>Antibodies, Viral (immunology)</term>
<term>Antibodies, Viral (therapeutic use)</term>
<term>Antigen-Antibody Complex (chemistry)</term>
<term>Betacoronavirus (chemistry)</term>
<term>Betacoronavirus (genetics)</term>
<term>Betacoronavirus (immunology)</term>
<term>Coronavirus Infections (drug therapy)</term>
<term>Coronavirus Infections (immunology)</term>
<term>Coronavirus Infections (prevention & control)</term>
<term>Coronavirus Infections (therapy)</term>
<term>Coronavirus Infections (virology)</term>
<term>Cryoelectron Microscopy (MeSH)</term>
<term>Crystallography, X-Ray (MeSH)</term>
<term>Host Microbial Interactions (immunology)</term>
<term>Humans (MeSH)</term>
<term>Models, Molecular (MeSH)</term>
<term>Neutralization Tests (MeSH)</term>
<term>Pandemics (MeSH)</term>
<term>Peptidyl-Dipeptidase A (chemistry)</term>
<term>Pneumonia, Viral (immunology)</term>
<term>Pneumonia, Viral (therapy)</term>
<term>Pneumonia, Viral (virology)</term>
<term>Receptors, Virus (chemistry)</term>
<term>Spike Glycoprotein, Coronavirus (chemistry)</term>
<term>Spike Glycoprotein, Coronavirus (genetics)</term>
<term>Spike Glycoprotein, Coronavirus (immunology)</term>
<term>Viral Vaccines (immunology)</term>
<term>Viral Vaccines (therapeutic use)</term>
<term>Virus Internalization (MeSH)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr">
<term>Anticorps antiviraux (immunologie)</term>
<term>Anticorps antiviraux (usage thérapeutique)</term>
<term>Anticorps monoclonaux (immunologie)</term>
<term>Anticorps neutralisants (immunologie)</term>
<term>Anticorps neutralisants (usage thérapeutique)</term>
<term>Betacoronavirus (composition chimique)</term>
<term>Betacoronavirus (génétique)</term>
<term>Betacoronavirus (immunologie)</term>
<term>Complexe antigène-anticorps (composition chimique)</term>
<term>Cristallographie aux rayons X (MeSH)</term>
<term>Cryomicroscopie électronique (MeSH)</term>
<term>Glycoprotéine de spicule des coronavirus (composition chimique)</term>
<term>Glycoprotéine de spicule des coronavirus (génétique)</term>
<term>Glycoprotéine de spicule des coronavirus (immunologie)</term>
<term>Humains (MeSH)</term>
<term>Infections à coronavirus (immunologie)</term>
<term>Infections à coronavirus (prévention et contrôle)</term>
<term>Infections à coronavirus (thérapie)</term>
<term>Infections à coronavirus (traitement médicamenteux)</term>
<term>Infections à coronavirus (virologie)</term>
<term>Interactions hôte-microbes (immunologie)</term>
<term>Modèles moléculaires (MeSH)</term>
<term>Pandémies (MeSH)</term>
<term>Peptidyl-Dipeptidase A (composition chimique)</term>
<term>Pneumopathie virale (immunologie)</term>
<term>Pneumopathie virale (thérapie)</term>
<term>Pneumopathie virale (virologie)</term>
<term>Pénétration virale (MeSH)</term>
<term>Récepteurs viraux (composition chimique)</term>
<term>Site allostérique (MeSH)</term>
<term>Séquence d'acides aminés (MeSH)</term>
<term>Tests de neutralisation (MeSH)</term>
<term>Vaccins antiviraux (immunologie)</term>
<term>Vaccins antiviraux (usage thérapeutique)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en">
<term>Antigen-Antibody Complex</term>
<term>Peptidyl-Dipeptidase A</term>
<term>Receptors, Virus</term>
<term>Spike Glycoprotein, Coronavirus</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en">
<term>Spike Glycoprotein, Coronavirus</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en">
<term>Antibodies, Monoclonal</term>
<term>Antibodies, Neutralizing</term>
<term>Antibodies, Viral</term>
<term>Spike Glycoprotein, Coronavirus</term>
<term>Viral Vaccines</term>
</keywords>
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<term>Antibodies, Neutralizing</term>
<term>Antibodies, Viral</term>
<term>Viral Vaccines</term>
</keywords>
<keywords scheme="MESH" qualifier="chemistry" xml:lang="en">
<term>Betacoronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="composition chimique" xml:lang="fr">
<term>Betacoronavirus</term>
<term>Complexe antigène-anticorps</term>
<term>Glycoprotéine de spicule des coronavirus</term>
<term>Peptidyl-Dipeptidase A</term>
<term>Récepteurs viraux</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en">
<term>Coronavirus Infections</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en">
<term>Betacoronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr">
<term>Betacoronavirus</term>
<term>Glycoprotéine de spicule des coronavirus</term>
</keywords>
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<term>Anticorps antiviraux</term>
<term>Anticorps monoclonaux</term>
<term>Anticorps neutralisants</term>
<term>Betacoronavirus</term>
<term>Glycoprotéine de spicule des coronavirus</term>
<term>Infections à coronavirus</term>
<term>Interactions hôte-microbes</term>
<term>Pneumopathie virale</term>
<term>Vaccins antiviraux</term>
</keywords>
<keywords scheme="MESH" qualifier="immunology" xml:lang="en">
<term>Betacoronavirus</term>
<term>Coronavirus Infections</term>
<term>Host Microbial Interactions</term>
<term>Pneumonia, Viral</term>
</keywords>
<keywords scheme="MESH" qualifier="prevention & control" xml:lang="en">
<term>Coronavirus Infections</term>
</keywords>
<keywords scheme="MESH" qualifier="prévention et contrôle" xml:lang="fr">
<term>Infections à coronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="therapy" xml:lang="en">
<term>Coronavirus Infections</term>
<term>Pneumonia, Viral</term>
</keywords>
<keywords scheme="MESH" qualifier="thérapie" xml:lang="fr">
<term>Infections à coronavirus</term>
<term>Pneumopathie virale</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr">
<term>Infections à coronavirus</term>
</keywords>
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<term>Anticorps antiviraux</term>
<term>Anticorps neutralisants</term>
<term>Vaccins antiviraux</term>
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<term>Infections à coronavirus</term>
<term>Pneumopathie virale</term>
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<keywords scheme="MESH" qualifier="virology" xml:lang="en">
<term>Coronavirus Infections</term>
<term>Pneumonia, Viral</term>
</keywords>
<keywords scheme="MESH" xml:lang="en">
<term>Allosteric Site</term>
<term>Amino Acid Sequence</term>
<term>Cryoelectron Microscopy</term>
<term>Crystallography, X-Ray</term>
<term>Humans</term>
<term>Models, Molecular</term>
<term>Neutralization Tests</term>
<term>Pandemics</term>
<term>Virus Internalization</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr">
<term>Cristallographie aux rayons X</term>
<term>Cryomicroscopie électronique</term>
<term>Humains</term>
<term>Modèles moléculaires</term>
<term>Pandémies</term>
<term>Pénétration virale</term>
<term>Site allostérique</term>
<term>Séquence d'acides aminés</term>
<term>Tests de neutralisation</term>
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<front>
<div type="abstract" xml:lang="en">There are as yet no licensed therapeutics for the COVID-19 pandemic. The causal coronavirus (SARS-CoV-2) binds host cells via a trimeric spike whose receptor binding domain (RBD) recognizes angiotensin-converting enzyme 2, initiating conformational changes that drive membrane fusion. We find that the monoclonal antibody CR3022 binds the RBD tightly, neutralizing SARS-CoV-2, and report the crystal structure at 2.4 Å of the Fab/RBD complex. Some crystals are suitable for screening for entry-blocking inhibitors. The highly conserved, structure-stabilizing CR3022 epitope is inaccessible in the prefusion spike, suggesting that CR3022 binding facilitates conversion to the fusion-incompetent post-fusion state. Cryogenic electron microscopy (cryo-EM) analysis confirms that incubation of spike with CR3022 Fab leads to destruction of the prefusion trimer. Presentation of this cryptic epitope in an RBD-based vaccine might advantageously focus immune responses. Binders at this epitope could be useful therapeutically, possibly in synergy with an antibody that blocks receptor attachment.</div>
</front>
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<MedlineCitation Status="MEDLINE" Owner="NLM">
<PMID Version="1">32585135</PMID>
<DateCompleted>
<Year>2020</Year>
<Month>09</Month>
<Day>21</Day>
</DateCompleted>
<DateRevised>
<Year>2020</Year>
<Month>10</Month>
<Day>22</Day>
</DateRevised>
<Article PubModel="Print-Electronic">
<Journal>
<ISSN IssnType="Electronic">1934-6069</ISSN>
<JournalIssue CitedMedium="Internet">
<Volume>28</Volume>
<Issue>3</Issue>
<PubDate>
<Year>2020</Year>
<Month>09</Month>
<Day>09</Day>
</PubDate>
</JournalIssue>
<Title>Cell host & microbe</Title>
<ISOAbbreviation>Cell Host Microbe</ISOAbbreviation>
</Journal>
<ArticleTitle>Neutralization of SARS-CoV-2 by Destruction of the Prefusion Spike.</ArticleTitle>
<Pagination>
<MedlinePgn>445-454.e6</MedlinePgn>
</Pagination>
<ELocationID EIdType="pii" ValidYN="Y">S1931-3128(20)30351-6</ELocationID>
<ELocationID EIdType="doi" ValidYN="Y">10.1016/j.chom.2020.06.010</ELocationID>
<Abstract>
<AbstractText>There are as yet no licensed therapeutics for the COVID-19 pandemic. The causal coronavirus (SARS-CoV-2) binds host cells via a trimeric spike whose receptor binding domain (RBD) recognizes angiotensin-converting enzyme 2, initiating conformational changes that drive membrane fusion. We find that the monoclonal antibody CR3022 binds the RBD tightly, neutralizing SARS-CoV-2, and report the crystal structure at 2.4 Å of the Fab/RBD complex. Some crystals are suitable for screening for entry-blocking inhibitors. The highly conserved, structure-stabilizing CR3022 epitope is inaccessible in the prefusion spike, suggesting that CR3022 binding facilitates conversion to the fusion-incompetent post-fusion state. Cryogenic electron microscopy (cryo-EM) analysis confirms that incubation of spike with CR3022 Fab leads to destruction of the prefusion trimer. Presentation of this cryptic epitope in an RBD-based vaccine might advantageously focus immune responses. Binders at this epitope could be useful therapeutically, possibly in synergy with an antibody that blocks receptor attachment.</AbstractText>
<CopyrightInformation>Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.</CopyrightInformation>
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<LastName>Huo</LastName>
<ForeName>Jiandong</ForeName>
<Initials>J</Initials>
<AffiliationInfo>
<Affiliation>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK; The Rosalind Franklin Institute, Harwell Campus, OX11 0FA, UK; Protein Production UK, Research Complex at Harwell, Harwell Science & Innovation Campus, Didcot, OX11 0FA, UK.</Affiliation>
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<LastName>Zhao</LastName>
<ForeName>Yuguang</ForeName>
<Initials>Y</Initials>
<AffiliationInfo>
<Affiliation>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK.</Affiliation>
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<ForeName>Tiong Kit</ForeName>
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<Affiliation>National Infection Service, Public Health England, Porton Down, Salisbury, SP4 0JG, UK.</Affiliation>
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<ForeName>Julia A</ForeName>
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<LastName>Supasa</LastName>
<ForeName>Piyada</ForeName>
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<Affiliation>Nuffield Department of Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.</Affiliation>
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<Affiliation>Nuffield Department of Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK; Dengue Hemorrhagic Fever Research Unit, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 73170, Thailand.</Affiliation>
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<ForeName>Gavin R</ForeName>
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<LastName>Owens</LastName>
<ForeName>Raymond J</ForeName>
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<AffiliationInfo>
<Affiliation>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK; The Rosalind Franklin Institute, Harwell Campus, OX11 0FA, UK; Protein Production UK, Research Complex at Harwell, Harwell Science & Innovation Campus, Didcot, OX11 0FA, UK.</Affiliation>
</AffiliationInfo>
</Author>
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<LastName>Stuart</LastName>
<ForeName>David I</ForeName>
<Initials>DI</Initials>
<AffiliationInfo>
<Affiliation>Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK; Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot, OX11 0DE, UK; Instruct-ERIC, Oxford House, Parkway Court, John Smith Drive, Oxford, OX4 2JY, UK. Electronic address: dave@strubi.ox.ac.uk.</Affiliation>
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<Language>eng</Language>
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<Grant>
<GrantID>MR/N00065X/1</GrantID>
<Acronym>MRC_</Acronym>
<Agency>Medical Research Council</Agency>
<Country>United Kingdom</Country>
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<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
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<ArticleDate DateType="Electronic">
<Year>2020</Year>
<Month>06</Month>
<Day>19</Day>
</ArticleDate>
</Article>
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<Country>United States</Country>
<MedlineTA>Cell Host Microbe</MedlineTA>
<NlmUniqueID>101302316</NlmUniqueID>
<ISSNLinking>1931-3128</ISSNLinking>
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<Chemical>
<RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000911">Antibodies, Monoclonal</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D057134">Antibodies, Neutralizing</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000914">Antibodies, Viral</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000936">Antigen-Antibody Complex</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="C000669933">COVID-19 vaccine</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D011991">Receptors, Virus</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D064370">Spike Glycoprotein, Coronavirus</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D014765">Viral Vaccines</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="C000657845">spike protein, SARS-CoV-2</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>EC 3.4.15.1</RegistryNumber>
<NameOfSubstance UI="D007703">Peptidyl-Dipeptidase A</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>EC 3.4.17.-</RegistryNumber>
<NameOfSubstance UI="C413524">angiotensin converting enzyme 2</NameOfSubstance>
</Chemical>
</ChemicalList>
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<SupplMeshName Type="Protocol" UI="C000705127">COVID-19 drug treatment</SupplMeshName>
<SupplMeshName Type="Organism" UI="C000656484">severe acute respiratory syndrome coronavirus 2</SupplMeshName>
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<CitationSubset>IM</CitationSubset>
<CommentsCorrectionsList>
<CommentsCorrections RefType="ErratumIn">
<RefSource>Cell Host Microbe. 2020 Sep 9;28(3):497</RefSource>
<PMID Version="1">32910920</PMID>
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<MeshHeadingList>
<MeshHeading>
<DescriptorName UI="D000495" MajorTopicYN="N">Allosteric Site</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D000595" MajorTopicYN="N">Amino Acid Sequence</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D000911" MajorTopicYN="N">Antibodies, Monoclonal</DescriptorName>
<QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D057134" MajorTopicYN="N">Antibodies, Neutralizing</DescriptorName>
<QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName>
<QualifierName UI="Q000627" MajorTopicYN="N">therapeutic use</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D000914" MajorTopicYN="N">Antibodies, Viral</DescriptorName>
<QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName>
<QualifierName UI="Q000627" MajorTopicYN="N">therapeutic use</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D000936" MajorTopicYN="N">Antigen-Antibody Complex</DescriptorName>
<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D000073640" MajorTopicYN="N">Betacoronavirus</DescriptorName>
<QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D018352" MajorTopicYN="N">Coronavirus Infections</DescriptorName>
<QualifierName UI="Q000188" MajorTopicYN="N">drug therapy</QualifierName>
<QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName>
<QualifierName UI="Q000517" MajorTopicYN="N">prevention & control</QualifierName>
<QualifierName UI="Q000628" MajorTopicYN="Y">therapy</QualifierName>
<QualifierName UI="Q000821" MajorTopicYN="N">virology</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D020285" MajorTopicYN="N">Cryoelectron Microscopy</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D018360" MajorTopicYN="N">Crystallography, X-Ray</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D000076662" MajorTopicYN="N">Host Microbial Interactions</DescriptorName>
<QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D008958" MajorTopicYN="N">Models, Molecular</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D009500" MajorTopicYN="N">Neutralization Tests</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D058873" MajorTopicYN="N">Pandemics</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D007703" MajorTopicYN="N">Peptidyl-Dipeptidase A</DescriptorName>
<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D011024" MajorTopicYN="N">Pneumonia, Viral</DescriptorName>
<QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName>
<QualifierName UI="Q000628" MajorTopicYN="Y">therapy</QualifierName>
<QualifierName UI="Q000821" MajorTopicYN="N">virology</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D011991" MajorTopicYN="N">Receptors, Virus</DescriptorName>
<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D064370" MajorTopicYN="N">Spike Glycoprotein, Coronavirus</DescriptorName>
<QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D014765" MajorTopicYN="N">Viral Vaccines</DescriptorName>
<QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName>
<QualifierName UI="Q000627" MajorTopicYN="N">therapeutic use</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D053586" MajorTopicYN="N">Virus Internalization</DescriptorName>
</MeshHeading>
</MeshHeadingList>
<KeywordList Owner="NOTNLM">
<Keyword MajorTopicYN="Y">CR3022</Keyword>
<Keyword MajorTopicYN="Y">SARS-CoV-2</Keyword>
<Keyword MajorTopicYN="Y">X-ray crystallography</Keyword>
<Keyword MajorTopicYN="Y">antibody</Keyword>
<Keyword MajorTopicYN="Y">cryo-electron microscopy</Keyword>
<Keyword MajorTopicYN="Y">epitope</Keyword>
<Keyword MajorTopicYN="Y">neutralization</Keyword>
<Keyword MajorTopicYN="Y">receptor binding domain</Keyword>
<Keyword MajorTopicYN="Y">spike</Keyword>
<Keyword MajorTopicYN="Y">therapeutic</Keyword>
</KeywordList>
<CoiStatement>Declaration of Interests The authors declare no competing interests.</CoiStatement>
</MedlineCitation>
<PubmedData>
<History>
<PubMedPubDate PubStatus="received">
<Year>2020</Year>
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<li>Thaïlande</li>
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<li>Oxfordshire</li>
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<li>Oxford</li>
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<name sortKey="Owens, Raymond J" sort="Owens, Raymond J" uniqKey="Owens R" first="Raymond J" last="Owens">Raymond J. Owens</name>
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<name sortKey="Radecke, Julika" sort="Radecke, Julika" uniqKey="Radecke J" first="Julika" last="Radecke">Julika Radecke</name>
<name sortKey="Ren, Jingshan" sort="Ren, Jingshan" uniqKey="Ren J" first="Jingshan" last="Ren">Jingshan Ren</name>
<name sortKey="Rijal, Pramila" sort="Rijal, Pramila" uniqKey="Rijal P" first="Pramila" last="Rijal">Pramila Rijal</name>
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<name sortKey="Shah, Pranav N M" sort="Shah, Pranav N M" uniqKey="Shah P" first="Pranav N M" last="Shah">Pranav N M. Shah</name>
<name sortKey="Stuart, David I" sort="Stuart, David I" uniqKey="Stuart D" first="David I" last="Stuart">David I. Stuart</name>
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<name sortKey="Tan, Tiong Kit" sort="Tan, Tiong Kit" uniqKey="Tan T" first="Tiong Kit" last="Tan">Tiong Kit Tan</name>
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<name sortKey="Tree, Julia A" sort="Tree, Julia A" uniqKey="Tree J" first="Julia A" last="Tree">Julia A. Tree</name>
<name sortKey="Zhao, Yuguang" sort="Zhao, Yuguang" uniqKey="Zhao Y" first="Yuguang" last="Zhao">Yuguang Zhao</name>
<name sortKey="Zhou, Daming" sort="Zhou, Daming" uniqKey="Zhou D" first="Daming" last="Zhou">Daming Zhou</name>
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<name sortKey="Mongkolsapaya, Juthathip" sort="Mongkolsapaya, Juthathip" uniqKey="Mongkolsapaya J" first="Juthathip" last="Mongkolsapaya">Juthathip Mongkolsapaya</name>
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