The antigenic anatomy of SARS-CoV-2 receptor binding domain

Cell. 2021 Apr 15;184(8):2183-2200.e22. doi: 10.1016/j.cell.2021.02.032. Epub 2021 Feb 18.


Antibodies are crucial to immune protection against SARS-CoV-2, with some in emergency use as therapeutics. Here, we identify 377 human monoclonal antibodies (mAbs) recognizing the virus spike and focus mainly on 80 that bind the receptor binding domain (RBD). We devise a competition data-driven method to map RBD binding sites. We find that although antibody binding sites are widely dispersed, neutralizing antibody binding is focused, with nearly all highly inhibitory mAbs (IC50 < 0.1 μg/mL) blocking receptor interaction, except for one that binds a unique epitope in the N-terminal domain. Many of these neutralizing mAbs use public V-genes and are close to germline. We dissect the structural basis of recognition for this large panel of antibodies through X-ray crystallography and cryoelectron microscopy of 19 Fab-antigen structures. We find novel binding modes for some potently inhibitory antibodies and demonstrate that strongly neutralizing mAbs protect, prophylactically or therapeutically, in animal models.

Keywords: coronavirus, SARS-CoV-2, anti-RBD antibody, receptor binding domain, antibody, immune responses, virus structure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology*
  • Antibodies, Neutralizing / immunology*
  • Antibodies, Viral / immunology*
  • Binding Sites, Antibody
  • CHO Cells
  • COVID-19 / immunology*
  • Chlorocebus aethiops
  • Cricetulus
  • Epitopes
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Models, Molecular
  • Protein Binding
  • Protein Structure, Tertiary
  • SARS-CoV-2 / immunology
  • Spike Glycoprotein, Coronavirus / immunology*
  • Vero Cells


  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Epitopes
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2