Binding of herpes simplex virus glycoprotein D to nectin-1 exploits host cell adhesion

Multiple surface envelope proteins are involved in the human herpes simplex virus type 1 entry and fusion. Among them, glycoprotein D (gD) has an important role by binding to the host receptors such as herpes virus entry mediator and nectin-1. Although the complex structure of gD with herpes virus entry mediator has been established, the binding mode of gD with the nectin-1 is elusive. Nectin-1 is a member of the immunoglobulin (Ig)-like (three Ig-like domains) cell adhesion molecules and is believed to form a homodimer to exert its functions. Here we report the complex structure of gD and nectin-1 (three Ig domains), revealing that gD binds the first Ig domain of nectin-1 in a similar mode to the nectin-1 homodimer interaction. The key amino acids responsible for nectin-1 dimerization are also used for gD/nectin-1 binding. This result indicates that binding of gD to nectin-1 would preclude the nectin-1 dimerization, consequently abolishing its cell adhesion function. Herpesvirus glycoprotein D binds to nectin 1 and the herpes virus entry mediator protein on the surface of host cells. In this study, Zhanget al. report the crystal structure of glycoprotein D in complex with the immunoglobulin-like domains of nectin 1, which suggests that binding of glycoprotein D to nectin 1 prevents nectin 1 dimerization.