HIV-1 envelope glycoprotein gp41 N-terminal heptad repeat deep pocket (gp41 NHR pocket)

The HIV-1 envelope glycoprotein gp41 N-terminal heptad repeat (NHR) deep pocket is a critical structural element involved in the fusion of the HIV-1 viral envelope with the host cell membrane (Chan, D. C., et al., 1997, Cell). During the fusion process, gp41 undergoes a major conformational change where three NHR helices form a central trimeric coiled-coil, and three C-terminal heptad repeat (CHR) helices wrap around them in an antiparallel fashion to form a six-helix bundle (6HB) (Jiang, S., et al., 1993, Nature). The NHR deep pocket is a highly conserved hydrophobic cavity at the base of the NHR coiled-coil that serves as a primary docking site for specific residues within the CHR region (He, Y., et al., 2008, Journal of Biological Chemistry). Because this pocket is essential for 6HB formation and subsequent viral entry, it is a major target for fusion inhibitors, including the FDA-approved peptide Enfuvirtide and second-generation inhibitors like Sifuvirtide and Albuvirtide (Lu, L., et al., 2016, Microbes and Infection). Small molecule inhibitors are also being actively developed to bind this pocket, aiming to disrupt the NHR-CHR interaction and prevent the virus from infecting host CD4+ T-cells (Zhao, Q., et al., 2013, AIDS Reviews).

Other names

gp41 hydrophobic pocketgp41 NHR-CHR interface pocketgp41 fusion pocketgp41 N-terminal heptad repeat (NHR) pocketgp41 coiled-coil cavity

Fusion inhibition by binding to the NHR coiled-coil pocket, preventing the interaction with the CHR region and subsequent formation of the six-helix bundle required for viral-host membrane fusion.