Structural basis of neutralization by a human anti-severe acute respiratory syndrome spike protein antibody, 80R

J Biol Chem. 2006 Nov 10;281(45):34610-6. doi: 10.1074/jbc.M603275200. Epub 2006 Sep 5.

Abstract

Severe acute respiratory syndrome (SARS) is a newly emerged infectious disease that caused pandemic spread in 2003. The etiological agent of SARS is a novel coronavirus (SARS-CoV). The coronaviral surface spike protein S is a type I transmembrane glycoprotein that mediates initial host binding via the cell surface receptor angiotensin-converting enzyme 2 (ACE2), as well as the subsequent membrane fusion events required for cell entry. Here we report the crystal structure of the S1 receptor binding domain (RBD) in complex with a neutralizing antibody, 80R, at 2.3 A resolution, as well as the structure of the uncomplexed S1 RBD at 2.2 A resolution. We show that the 80R-binding epitope on the S1 RBD overlaps very closely with the ACE2-binding site, providing a rationale for the strong binding and broad neutralizing ability of the antibody. We provide a structural basis for the differential effects of certain mutations in the spike protein on 80R versus ACE2 binding, including escape mutants, which should facilitate the design of immunotherapeutics to treat a future SARS outbreak. We further show that the RBD of S1 forms dimers via an extensive interface that is disrupted in receptor- and antibody-bound crystal structures, and we propose a role for the dimer in virus stability and infectivity.

Publication types

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

MeSH terms

  • Antibodies, Viral / immunology
  • Antibodies, Viral / metabolism*
  • Binding Sites
  • Crystallization
  • Crystallography, X-Ray
  • Humans
  • Membrane Glycoproteins / chemistry*
  • Membrane Glycoproteins / immunology
  • Membrane Glycoproteins / metabolism*
  • Models, Molecular
  • Neutralization Tests
  • Protein Binding
  • Protein Structure, Tertiary
  • SARS Virus / metabolism*
  • Severe Acute Respiratory Syndrome
  • Spike Glycoprotein, Coronavirus
  • Viral Envelope Proteins / chemistry*
  • Viral Envelope Proteins / immunology
  • Viral Envelope Proteins / metabolism*

Substances

  • Antibodies, Viral
  • Membrane Glycoproteins
  • Spike Glycoprotein, Coronavirus
  • Viral Envelope Proteins

Associated data

  • PDB/2GHV
  • PDB/2GHW