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

Abstract:

: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.

journal_name

PLoS Pathog

journal_title

PLoS pathogens

authors

Wu NC,Yuan M,Bangaru S,Huang D,Zhu X,Lee CD,Turner HL,Peng L,Yang L,Burton DR,Nemazee D,Ward AB,Wilson IA

doi

10.1371/journal.ppat.1009089

subject

Has Abstract

pub_date

2020-12-04 00:00:00

pages

e1009089

issue

12

eissn

1553-7366

issn

1553-7374

pii

PPATHOGENS-D-20-02083

journal_volume

16

pub_type

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