Structural insight into SARS-CoV-2 neutralizing antibodies and modulation of syncytia

Cell. 2021 Jun 10;184(12):3192-3204.e16. doi: 10.1016/j.cell.2021.04.033. Epub 2021 Apr 24.


Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is initiated by binding of the viral Spike protein to host receptor angiotensin-converting enzyme 2 (ACE2), followed by fusion of viral and host membranes. Although antibodies that block this interaction are in emergency use as early coronavirus disease 2019 (COVID-19) therapies, the precise determinants of neutralization potency remain unknown. We discovered a series of antibodies that potently block ACE2 binding but exhibit divergent neutralization efficacy against the live virus. Strikingly, these neutralizing antibodies can inhibit or enhance Spike-mediated membrane fusion and formation of syncytia, which are associated with chronic tissue damage in individuals with COVID-19. As revealed by cryoelectron microscopy, multiple structures of Spike-antibody complexes have distinct binding modes that not only block ACE2 binding but also alter the Spike protein conformational cycle triggered by ACE2 binding. We show that stabilization of different Spike conformations leads to modulation of Spike-mediated membrane fusion with profound implications for COVID-19 pathology and immunity.

Keywords: COVID-19; SARS-CoV; SARS-CoV-2; Spike protein; coronavirus; phage display; receptor binding domain (RBD); recombinant monoclonal antibody; syncytia.

Publication types

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

MeSH terms

  • Angiotensin-Converting Enzyme 2 / chemistry
  • Angiotensin-Converting Enzyme 2 / genetics
  • Angiotensin-Converting Enzyme 2 / immunology
  • Angiotensin-Converting Enzyme 2 / metabolism
  • Animals
  • Antibodies, Neutralizing / chemistry*
  • Antibodies, Neutralizing / immunology
  • Antibodies, Neutralizing / metabolism
  • Antigen-Antibody Complex / chemistry
  • Antigen-Antibody Complex / metabolism
  • Binding Sites
  • CHO Cells
  • COVID-19 / pathology
  • COVID-19 / virology
  • Cricetinae
  • Cricetulus
  • Cryoelectron Microscopy
  • Giant Cells / cytology
  • Giant Cells / metabolism*
  • Humans
  • Membrane Fusion
  • Peptide Library
  • Protein Binding
  • Protein Domains
  • Protein Structure, Quaternary
  • SARS-CoV-2 / isolation & purification
  • SARS-CoV-2 / metabolism
  • Spike Glycoprotein, Coronavirus / chemistry*
  • Spike Glycoprotein, Coronavirus / immunology
  • Spike Glycoprotein, Coronavirus / metabolism


  • Antibodies, Neutralizing
  • Antigen-Antibody Complex
  • Peptide Library
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Angiotensin-Converting Enzyme 2