title: Structure of herpes simplex virus glycoprotein D bound to the human receptor nectin-1.
abstract: Binding of herpes simplex virus (HSV) glycoprotein D (gD) to a cell surface receptor is required to trigger membrane fusion during entry into host cells. Nectin-1 is a cell adhesion molecule and the main HSV receptor in neurons and epithelial cells. We report the structure of gD bound to nectin-1 determined by x-ray crystallography to 4.0 Å resolution. The structure reveals that the nectin-1 binding site on gD differs from the binding site of the HVEM receptor. A surface on the first Ig-domain of nectin-1, which mediates homophilic interactions of Ig-like cell adhesion molecules, buries an area composed by residues from both the gD N- and C-terminal extensions. Phenylalanine 129, at the tip of the loop connecting β-strands F and G of nectin-1, protrudes into a groove on gD, which is otherwise occupied by C-terminal residues in the unliganded gD and by N-terminal residues in the gD/HVEM complex. Notably, mutation of Phe129 to alanine prevents nectin-1 binding to gD and HSV entry. Together these data are consistent with previous studies showing that gD disrupts the normal nectin-1 homophilic interactions. Furthermore, the structure of the complex supports a model in which gD-receptor binding triggers HSV entry through receptor-mediated displacement of the gD C-terminal region.
authors: Department of Biochemistry and Molecular Biology, IRBM P. Angeletti, Pomezia, Rome, Italy.
authors: Paolo
authors: P
authors: Di Giovine
authors: Ethan C
authors: EC
authors: Settembre
authors: Arjun K
authors: AK
authors: Bhargava
authors: Micah A
authors: MA
authors: Luftig
authors: Huan
authors: H
authors: Lou
authors: Gary H
authors: GH
authors: Cohen
authors: Roselyn J
authors: RJ
authors: Eisenberg
authors: Claude
authors: C
authors: Krummenacher
authors: Andrea
authors: A
authors: Carfi
mesh_terms: D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000737:chemistry* / Q000502:physiology; D006801:Humans; D000075983:Nectins; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011991:Receptors, Virus / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D053586:Virus Internalization
chemical_list: D015815:Cell Adhesion Molecules; C000619010:NECTIN1 protein, human; D000075983:Nectins; D011991:Receptors, Virus; D014759:Viral Envelope Proteins; C039447:glycoprotein D, Human herpesvirus 1