Structural mechanism of SARS-CoV-2 neutralization by two murine antibodies targeting the RBD

John M. Errico, Haiyan Zhao, Rita E. Chen, Zhuoming Liu, James Brett Case, Meisheng Ma, Aaron J. Schmitz, Michael J. Rau, James A.J. Fitzpatrick, Pei Yong Shi, Michael S. Diamond, Sean P.J. Whelan, Ali H. Ellebedy, Daved H. Fremont

Research output: Contribution to journalArticlepeer-review


The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has necessitated the rapid development of antibody-based therapies and vaccines as countermeasures. Here, we use cryoelectron microscopy (cryo-EM) to characterize two protective anti-SARS-CoV-2 murine monoclonal antibodies (mAbs) in complex with the spike protein, revealing similarities between epitopes targeted by human and murine B cells. The more neutralizing mAb, 2B04, binds the receptor-binding motif (RBM) of the receptor-binding domain (RBD) and competes with angiotensin-converting enzyme 2 (ACE2). By contrast, 2H04 binds adjacent to the RBM and does not compete for ACE2 binding. Naturally occurring sequence variants of SARS-CoV-2 and corresponding neutralization escape variants selected in vitro map to our structurally defined epitopes, suggesting that SARS-CoV-2 might evade therapeutic antibodies with a limited set of mutations, underscoring the importance of combination mAb therapeutics. Finally, we show that 2B04 neutralizes SARS-CoV-2 infection by preventing ACE2 engagement, whereas 2H04 reduces host cell attachment without directly disrupting ACE2-RBM interactions, providing distinct inhibitory mechanisms used by RBD-specific mAbs.

Original languageEnglish (US)
Article number109881
JournalCell Reports
Issue number4
StatePublished - Oct 26 2021


  • ACE2
  • COVID-19
  • RBD
  • SARS-CoV-2
  • antibody neutralization
  • biolayer interferometry
  • cryo-EM
  • spike
  • variants of concern

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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