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

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

Research output: Working paper

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 can 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 for cross-neutralizing epitopes on SARS-like viruses.Competing Interest StatementThe authors have declared no competing interest.
Original languageEnglish (US)
PublisherCold Spring Harbor Laboratory Press
Number of pages37
DOIs
StateIn preparation - Sep 21 2020

Publication series

NamebioRxiv
PublisherCold Spring Harbor Laboratory Press

Keywords

  • Coronavirus
  • COVID-19
  • severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
  • Novel coronavirus
  • 2019-nCoV
  • Pandemic

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    Wu, N. C., Yuan, M., Bangaru, S., Huang, D., Zhu, X., Lee, C-C. D., Turner, H. L., Peng, L., Yang, L., Nemazee, D., Ward, A. B., & Wilson, I. A. (2020). A natural mutation between SARS-CoV-2 and SARS-CoV determines neutralization by a cross-reactive antibody. (bioRxiv). Cold Spring Harbor Laboratory Press. https://doi.org/10.1101/2020.09.21.305441