Structure of herpes simplex virus glycoprotein D bound to the human receptor nectin-1.

By Di Giovine, Paolo; Settembre, Ethan C.; Bhargava, Arjun K.; Luftig, Micah A.; Lou, Huan; Cohen, Gary H.; Eisenberg, Roselyn J.; Krummenacher, Claude; Carfi, Andrea
From PLoS Pathogens (2011), 7(9), e1002277. Language: English, Database: CAPLUS, DOI:10.1371/journal.ppat.1002277

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 mol. and the main HSV receptor in neurons and epithelial cells. The authors report the structure of gD bound to nectin-1 detd. by x-ray crystallog. to 4.0 Å resoln. 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 mols., 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.