Structure of unliganded HSV gD reveals a mechanism for receptor-mediated activation of virus entry

EMBO J. 2005 Dec 7;24(23):4144-53. doi: 10.1038/sj.emboj.7600875. Epub 2005 Nov 17.

Abstract

Herpes simplex virus (HSV) entry into cells requires binding of the envelope glycoprotein D (gD) to one of several cell surface receptors. The 50 C-terminal residues of the gD ectodomain are essential for virus entry, but not for receptor binding. We have determined the structure of an unliganded gD molecule that includes these C-terminal residues. The structure reveals that the C-terminus is anchored near the N-terminal region and masks receptor-binding sites. Locking the C-terminus in the position observed in the crystals by an intramolecular disulfide bond abolished receptor binding and virus entry, demonstrating that this region of gD moves upon receptor binding. Similarly, a point mutant that would destabilize the C-terminus structure was nonfunctional for entry, despite increased affinity for receptors. We propose that a controlled displacement of the gD C-terminus upon receptor binding is an essential feature of HSV entry, ensuring the timely activation of membrane fusion.

Publication types

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

MeSH terms

  • Dimerization
  • Herpes Simplex / metabolism
  • Ligands
  • Protein Structure, Tertiary
  • Receptors, Virus / physiology*
  • Simplexvirus / metabolism
  • Simplexvirus / pathogenicity*
  • Simplexvirus / physiology*
  • Tryptophan / metabolism
  • Viral Envelope Proteins / chemistry*
  • Viral Envelope Proteins / metabolism*

Substances

  • Ligands
  • Receptors, Virus
  • Viral Envelope Proteins
  • glycoprotein D, Human herpesvirus 1
  • simplexvirus receptor
  • Tryptophan

Associated data

  • PDB/2C36
  • PDB/2C3A