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

Joyce, M. G.; Sankhala, R. S.; Chen, W.-H.; Choe, M.; Bai, H.; Hajduczki, A.; Yan, L.; Sterling, S. L.; Peterson, C.; Green, E. C.; Smith, C.; de Val, N.; Amare, M.; Scott, P.; Laing, E. D.; Broder, C. C.; Rolland, M.; Michael, N. L.; Modjarrad, K.

doi:10.1101/2020.03.15.992883

bioRxiv · 10.1101/2020.03.15.992883

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

Joyce, M. G.·Sankhala, R. S.·Chen, W.-H.·Choe, M.·Bai, H.·Hajduczki, A.·Yan, L.·Sterling, S. L.·Peterson, C.·Green, E. C.·Smith, C.·de Val, N.·Amare, M.·Scott, P.·Laing, E. D.·Broder, C. C.·Rolland, M.·Michael, N. L.·Modjarrad, K.

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Abstract

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 coronaviruss 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 [A]. 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. HIGHLIGHTSHigh 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.

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Joyce, M. G., Sankhala, R. S., Chen, W.-H., Choe, M., Bai, H., Hajduczki, A., Yan, L., Sterling, S. L., Peterson, C., Green, E. C., Smith, C., de Val, N., Amare, M., Scott, P., Laing, E. D., Broder, C. C., Rolland, M., Michael, N. L., Modjarrad, K.. 2020-03-17. A Cryptic Site of Vulnerability on the Receptor Binding Domain of the SARS-CoV-2 Spike Glycoprotein. https://doi.org/10.1101/2020.03.15.992883

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