title: Structure of unliganded HSV gD reveals a mechanism for receptor-mediated activation of virus entry.
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.
authors.affiliation: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Claude
authors.initials: C
authors.lastname: Krummenacher
authors.forename: Vinit M
authors.initials: VM
authors.lastname: Supekar
authors.forename: J Charles
authors.initials: JC
authors.lastname: Whitbeck
authors.forename: Eric
authors.initials: E
authors.lastname: Lazear
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Connolly
authors.forename: Roselyn J
authors.initials: RJ
authors.lastname: Eisenberg
authors.forename: Gary H
authors.initials: GH
authors.lastname: Cohen
authors.forename: Don C
authors.initials: DC
authors.lastname: Wiley
authors.forename: Andrea
authors.initials: A
authors.lastname: Carfí
mesh_terms: D019281:Dimerization; D006561:Herpes Simplex / Q000378:metabolism; D008024:Ligands; D017434:Protein Structure, Tertiary; D011991:Receptors, Virus / Q000502:physiology*; D018139:Simplexvirus / Q000378:metabolism / Q000472:pathogenicity* / Q000502:physiology*; D014364:Tryptophan / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D008024:Ligands; D011991:Receptors, Virus; D014759:Viral Envelope Proteins; C039447:glycoprotein D, Human herpesvirus 1; C049545:simplexvirus receptor; D014364:Tryptophan