A natural mutation between SARS-CoV-2 and SARS-CoV determines neutralization by a cross-reactive antibody

Wu, Nicholas C.; Yuan, Meng; Bangaru, Sandhya; Huang, Deli; Zhu, Xueyong; Lee, Chang-Chun D.; Turner, Hannah L.; Peng, Linghang; Yang, Linlin; Burton, Dennis R.; Nemazee, David; Ward, Andrew B.; Wilson, Ian A.; Diamond, ed., Michael S.

doi:10.1371/journal.ppat.1009089

A natural mutation between SARS-CoV-2 and SARS-CoV determines neutralization by a cross-reactive antibody

Journal Article · Fri Dec 04 00:00:00 EST 2020 · PLoS Pathogens

DOI:https://doi.org/10.1371/journal.ppat.1009089· OSTI ID:1777660

; ; ; ; ; ; ; Peng, Linghang; ; Burton, Dennis R.; Nemazee, David; ; ; Diamond, ed., Michael S.

Epitopes that are conserved among SARS-like coronaviruses are attractive targets for design of cross-reactive vaccines and therapeutics. CR3022 is a SARS-CoV neutralizing antibody to a highly conserved epitope on the receptor binding domain (RBD) on the spike protein that is able to cross-react with SARS-CoV-2, but with lower affinity. Using x-ray crystallography, mutagenesis, and binding experiments, we illustrate that of four amino acid differences in the CR3022 epitope between SARS-CoV-2 and SARS-CoV, a single mutation P384A fully determines the affinity difference. CR3022 does not neutralize SARS-CoV-2, but the increased affinity to SARS-CoV-2 P384A mutant now enables neutralization with a similar potency to SARS-CoV. We further investigated CR3022 interaction with the SARS-CoV spike protein by negative-stain EM and cryo-EM. Three CR3022 Fabs bind per trimer with the RBD observed in different up-conformations due to considerable flexibility of the RBD. In one of these conformations, quaternary interactions are made by CR3022 to the N-terminal domain (NTD) of an adjacent subunit. Overall, this study provides insights into antigenic variation and potential cross-neutralizing epitopes on SARS-like viruses.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL); The Scripps Research Institute, La Jolla, CA (United States)

Sponsoring Organization:: Bill and Melinda Gates Foundation; National Institutes of Health 9NIH); USDOE; USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1777660

Alternate ID(s):: OSTI ID: 1731031
OSTI ID: 1903967

Journal Information:: PLoS Pathogens, Journal Name: PLoS Pathogens Journal Issue: 12 Vol. 16; ISSN 1553-7374

Publisher:: Public Library of Science (PLoS)Copyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
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antigens
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A natural mutation between SARS-CoV-2 and SARS-CoV determines neutralization by a cross-reactive antibody

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