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A Cryptic Site of Vulnerability on the Receptor Binding Domain of the SARS-CoV-2 Spike Glycoprotein

M. Gordon Joyce, Rajeshwer S. Sankhala, Wei-Hung Chen, Misook Choe, Hongjun Bai, Agnes Hajduczki, Lianying Yan, Spencer L. Sterling, Caroline E. Peterson, Ethan C. Green, Clayton Smith, Natalia de Val, Mihret Amare, Paul Scott, Eric D. Laing, Christopher C. Broder, Morgane Rolland, Nelson L. Michael, Kayvon Modjarrad
doi: https://doi.org/10.1101/2020.03.15.992883
M. Gordon Joyce
1Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA
2U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA
3Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA
7Center for Infectious Diseases Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA
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  • For correspondence: gjoyce@eidresearch.org kayvon.modjarrad.civ@mail.mil
Rajeshwer S. Sankhala
1Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA
2U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA
3Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA
7Center for Infectious Diseases Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA
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Wei-Hung Chen
1Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA
2U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA
3Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA
7Center for Infectious Diseases Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA
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Misook Choe
1Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA
2U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA
3Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA
7Center for Infectious Diseases Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA
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Hongjun Bai
1Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA
2U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA
3Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA
7Center for Infectious Diseases Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA
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Agnes Hajduczki
1Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA
2U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA
3Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA
7Center for Infectious Diseases Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA
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Lianying Yan
4Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD, USA, Bethesda, MD, USA
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Spencer L. Sterling
4Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD, USA, Bethesda, MD, USA
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Caroline E. Peterson
1Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA
2U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA
3Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA
7Center for Infectious Diseases Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA
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Ethan C. Green
1Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA
4Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD, USA, Bethesda, MD, USA
7Center for Infectious Diseases Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA
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Clayton Smith
5Center for Molecular Microscopy, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA
6Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD, USA
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Natalia de Val
5Center for Molecular Microscopy, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA
6Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD, USA
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Mihret Amare
1Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA
3Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA
7Center for Infectious Diseases Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA
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Paul Scott
1Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA
7Center for Infectious Diseases Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA
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Eric D. Laing
4Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD, USA, Bethesda, MD, USA
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Christopher C. Broder
4Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD, USA, Bethesda, MD, USA
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Morgane Rolland
1Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA
2U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA
3Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA
7Center for Infectious Diseases Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA
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Nelson L. Michael
7Center for Infectious Diseases Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA
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Kayvon Modjarrad
1Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA
7Center for Infectious Diseases Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA
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  • For correspondence: gjoyce@eidresearch.org kayvon.modjarrad.civ@mail.mil
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SUMMARY

SARS-CoV-2 is a zoonotic virus that has caused a pandemic of severe respiratory disease—COVID-19— within several months of its initial identification. Comparable to the first SARS-CoV, this novel coronavirus’s surface Spike (S) glycoprotein mediates cell entry via the human ACE-2 receptor, and, thus, is the principal target for the development of vaccines and immunotherapeutics. Molecular information on the SARS-CoV-2 S glycoprotein remains limited. Here we report the crystal structure of the SARS-CoV-2 S receptor-binding-domain (RBD) at a the highest resolution to date, of 1.95 Å. We identified a set of SARS-reactive monoclonal antibodies with cross-reactivity to SARS-CoV-2 RBD and other betacoronavirus S glycoproteins. One of these antibodies, CR3022, was previously shown to synergize with antibodies that target the ACE-2 binding site on the SARS-CoV RBD and reduce viral escape capacity. We determined the structure of CR3022, in complex with the SARS-CoV-2 RBD, and defined a broadly reactive epitope that is highly conserved across betacoronaviruses. This epitope is inaccessible in the “closed” prefusion S structure, but is accessible in “open” conformations. This first-ever resolution of a human antibody in complex with SARS-CoV-2 and the broad reactivity of this set of antibodies to a conserved betacoronavirus epitope will allow antigenic assessment of vaccine candidates, and provide a framework for accelerated vaccine, immunotherapeutic and diagnostic strategies against SARS-CoV-2 and related betacoronaviruses.

HIGHLIGHTS High resolution structure of the SARS-CoV-2 Receptor-Binding-Domain (RBD).

Recognition of the SARS-CoV-2 RBD by SARS-CoV antibodies.

Structure of the SARS-COV-2 RBD in complex with antibody CR3022.

Identification of a cryptic site of vulnerability on the SARS-CoV-2 Spike.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.
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Posted March 17, 2020.
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A Cryptic Site of Vulnerability on the Receptor Binding Domain of the SARS-CoV-2 Spike Glycoprotein
M. Gordon Joyce, Rajeshwer S. Sankhala, Wei-Hung Chen, Misook Choe, Hongjun Bai, Agnes Hajduczki, Lianying Yan, Spencer L. Sterling, Caroline E. Peterson, Ethan C. Green, Clayton Smith, Natalia de Val, Mihret Amare, Paul Scott, Eric D. Laing, Christopher C. Broder, Morgane Rolland, Nelson L. Michael, Kayvon Modjarrad
bioRxiv 2020.03.15.992883; doi: https://doi.org/10.1101/2020.03.15.992883
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A Cryptic Site of Vulnerability on the Receptor Binding Domain of the SARS-CoV-2 Spike Glycoprotein
M. Gordon Joyce, Rajeshwer S. Sankhala, Wei-Hung Chen, Misook Choe, Hongjun Bai, Agnes Hajduczki, Lianying Yan, Spencer L. Sterling, Caroline E. Peterson, Ethan C. Green, Clayton Smith, Natalia de Val, Mihret Amare, Paul Scott, Eric D. Laing, Christopher C. Broder, Morgane Rolland, Nelson L. Michael, Kayvon Modjarrad
bioRxiv 2020.03.15.992883; doi: https://doi.org/10.1101/2020.03.15.992883

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