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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.

SUBMITTER: Wu NC 

PROVIDER: S-EPMC7744049 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Wu Nicholas C NC   Yuan Meng M   Bangaru Sandhya S   Huang Deli D   Zhu Xueyong X   Lee Chang-Chun D CD   Turner Hannah L HL   Peng Linghang L   Yang Linlin L   Burton Dennis R DR   Nemazee David D   Ward Andrew B AB   Wilson Ian A IA  

PLoS pathogens 20201204 12


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  ...[more]

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