Transient opening of trimeric prefusion RSV F proteins

Nat Commun. 2019 May 8;10(1):2105. doi: 10.1038/s41467-019-09807-5.

Abstract

The respiratory syncytial virus (RSV) F glycoprotein is a class I fusion protein that mediates viral entry and is a major target of neutralizing antibodies. Structures of prefusion forms of RSV F, as well as other class I fusion proteins, have revealed compact trimeric arrangements, yet whether these trimeric forms can transiently open remains unknown. Here, we perform structural and biochemical studies on a recently isolated antibody, CR9501, and demonstrate that it enhances the opening of prefusion-stabilized RSV F trimers. The 3.3 Å crystal structure of monomeric RSV F bound to CR9501, combined with analysis of over 25 previously determined RSV F structures, reveals a breathing motion of the prefusion conformation. We also demonstrate that full-length RSV F trimers transiently open and dissociate on the cell surface. Collectively, these findings have implications for the function of class I fusion proteins, as well as antibody prophylaxis and vaccine development for RSV.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Neutralizing / chemistry
  • Antibodies, Neutralizing / immunology
  • Antibodies, Neutralizing / metabolism*
  • Antibodies, Viral / chemistry
  • Antibodies, Viral / immunology
  • Antibodies, Viral / metabolism*
  • B-Lymphocytes / virology
  • Chlorocebus aethiops
  • Computer Simulation
  • Crystallography, X-Ray
  • Drug Development
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Models, Molecular
  • Protein Multimerization / physiology
  • Respiratory Syncytial Virus Infections / immunology
  • Respiratory Syncytial Virus Infections / prevention & control
  • Respiratory Syncytial Virus Infections / virology
  • Respiratory Syncytial Virus Vaccines / immunology
  • Respiratory Syncytial Virus, Human / isolation & purification
  • Respiratory Syncytial Virus, Human / physiology*
  • Vero Cells
  • Viral Fusion Proteins / chemistry
  • Viral Fusion Proteins / immunology
  • Viral Fusion Proteins / metabolism*

Substances

  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Respiratory Syncytial Virus Vaccines
  • Viral Fusion Proteins