tetano
Editor, Senior Moderator
PLoS Pathog
. 2020 Dec 4;16(12):e1009089.
doi: 10.1371/journal.ppat.1009089. Online ahead of print.
A natural mutation between SARS-CoV-2 and SARS-CoV determines neutralization by a cross-reactive antibody
Nicholas C Wu[SUP] 1 2 [/SUP], Meng Yuan[SUP] 3 [/SUP], Sandhya Bangaru[SUP] 3 [/SUP], Deli Huang[SUP] 4 [/SUP], Xueyong Zhu[SUP] 3 [/SUP], Chang-Chun D Lee[SUP] 3 [/SUP], Hannah L Turner[SUP] 3 [/SUP], Linghang Peng[SUP] 4 [/SUP], Linlin Yang[SUP] 4 [/SUP], Dennis R Burton[SUP] 4 5 6 7 [/SUP], David Nemazee[SUP] 4 [/SUP], Andrew B Ward[SUP] 3 5 6 [/SUP], Ian A Wilson[SUP] 3 5 6 8 [/SUP]
Affiliations
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.
. 2020 Dec 4;16(12):e1009089.
doi: 10.1371/journal.ppat.1009089. Online ahead of print.
A natural mutation between SARS-CoV-2 and SARS-CoV determines neutralization by a cross-reactive antibody
Nicholas C Wu[SUP] 1 2 [/SUP], Meng Yuan[SUP] 3 [/SUP], Sandhya Bangaru[SUP] 3 [/SUP], Deli Huang[SUP] 4 [/SUP], Xueyong Zhu[SUP] 3 [/SUP], Chang-Chun D Lee[SUP] 3 [/SUP], Hannah L Turner[SUP] 3 [/SUP], Linghang Peng[SUP] 4 [/SUP], Linlin Yang[SUP] 4 [/SUP], Dennis R Burton[SUP] 4 5 6 7 [/SUP], David Nemazee[SUP] 4 [/SUP], Andrew B Ward[SUP] 3 5 6 [/SUP], Ian A Wilson[SUP] 3 5 6 8 [/SUP]
Affiliations
- PMID: 33275640
- DOI: 10.1371/journal.ppat.1009089
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.