View the Current Issue

Article

  • The EMBO Journal (2005) 24, 4144 - 4153
  • doi:10.1038/sj.emboj.7600875

Published online: 17 November 2005

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

Claude Krummenacher1, Vinit M Supekar2, J Charles Whitbeck3, Eric Lazear1, Sarah A Connolly1, Roselyn J Eisenberg3, Gary H Cohen1, Don C Wiley4,a and Andrea Carfí2

  1. Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
  2. Biochemistry Department, IRBM P Angeletti, Pomezia, Rome, Italy
  3. Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
  4. Children's Hospital Laboratory of Molecular Medicine, Boston, MA, USA

Correspondence to:

Andrea Carfí, Department of Biochemistry, IRBM P Angeletti, Via Pontina Km 30,600, 10040 Pomezia, Rome, Italy. Tel.: +39 06 9109 3550; Fax: +39 06 9109 3225; E-mail: andrea_carfi@merck.com

aDeceased

Received 25 August 2005; Accepted 25 October 2005

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.

  • Keywords:

    • glycoprotein D,
    • herpes simplex virus,
    • receptor binding,
    • viral entry