Human immunodeficiency virus type 1 glycoprotein 41 N-terminal heptad repeat trimer pocket (gp41 N-trimer pocket)

The HIV-1 gp41 N-trimer pocket is a highly conserved hydrophobic cavity located at the base of the N-terminal heptad repeat (NHR) coiled-coil trimer of the gp41 transmembrane glycoprotein (Chan et al., 1997). This pocket is a critical structural element in the HIV-1 entry mechanism, serving as the essential docking site for the C-terminal heptad repeat (CHR) during the formation of the post-fusion six-helix bundle (6HB) (Root et al., 2001). The assembly of the 6HB brings the viral and host cell membranes into close proximity, facilitating the membrane fusion required for viral RNA delivery (Eckert & Kim, 2001). Due to its vital role and high sequence conservation, the pocket is a primary target for fusion inhibitors designed to block viral infection (Liu et al., 2007). Therapeutic agents such as the peptides C34 and T-1249, as well as various experimental small molecules like ADS-J1, target this pocket to competitively inhibit the NHR-CHR interaction (He et al., 2008). While the first-generation inhibitor Enfuvirtide targets the NHR region, it does not bind directly to this pocket, making pocket-specific inhibitors a key focus for overcoming Enfuvirtide resistance (Eggink et al., 2011). Resistance to pocket-targeting drugs typically involves mutations within the NHR or CHR regions that reduce binding affinity while maintaining fusion competence (Wei et al., 2002). Ongoing research continues to explore this site for the development of long-acting and orally bioavailable entry inhibitors (Xu et al., 2019).

Other names

gp41 hydrophobic pocketNHR pocketgp41 N-terminal heptad repeat pocketgp41 N-trimer cavitygp41 hydrophobic groove

Fusion inhibition by competitive binding to the NHR pocket, preventing six-helix bundle (6HB) formation and viral-host membrane fusion.