Human immunodeficiency virus type 1 glycoprotein 41 N-terminal heptad repeat domain (NHR)

The Human immunodeficiency virus type 1 (HIV-1) glycoprotein 41 (gp41) N-terminal heptad repeat (NHR) domain is a critical structural component of the viral envelope's transmembrane subunit (Chan et al., 1997, Cell). It plays a central role in the fusion of the viral envelope with the host cell plasma membrane, a process initiated by the binding of the surface subunit gp120 to CD4 and coreceptors (Wild et al., 1994, PNAS). Structurally, three NHR helices form a central coiled-coil trimer that serves as a scaffold for the C-terminal heptad repeat (CHR) domains. The interaction between NHR and CHR results in a six-helix bundle (6HB) conformation, which provides the mechanical energy to pull the viral and cellular membranes together for fusion (Eggink et al., 2010, JBC). This domain is the primary target for fusion inhibitors, such as the FDA-approved peptide Enfuvirtide (Lalezari et al., 2003, NEJM). These inhibitors mimic the CHR region and bind to the hydrophobic grooves of the NHR trimer, preventing the endogenous CHR from binding and thereby arresting viral entry. Clinical challenges include the development of resistance through mutations in the NHR sequence and the requirement for parenteral administration of these peptide-based drugs.

Other names

HR1N-HRgp41 N-terminal heptad repeatHeptad repeat 1NHR domain

Fusion inhibition by binding to the hydrophobic grooves of the NHR trimer, which prevents the formation of the six-helix bundle (6HB) required for viral-host membrane fusion.