Open AccessA natural mutation between SARS-CoV-2 and SARS-CoV determines neutralization by a cross-reactive antibody
Author(s) -
Nicholas C. Wu,
Meng Yuan,
Sandhya Bangaru,
Deli Huang,
Xueyong Zhu,
Chang-Chun David Lee,
Hannah L. Turner,
Linghang Peng,
Linlin Yang,
Dennis R. Burton,
David Nemazee,
Andrew B. Ward,
Ian A. Wilson
Publication year - 2020
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1009089
Subject(s) - epitope , neutralization , mutagenesis , virology , mutant , antibody , coronavirus , mutation , covid-19 , plasma protein binding , chemistry , biology , protein structure , binding site , virus , genetics , biochemistry , gene , medicine , disease , pathology , infectious disease (medical specialty)
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.