HIV-1 envelope glycoprotein gp41 transmembrane domain (gp41 TMD)

The HIV-1 envelope glycoprotein gp41 transmembrane domain (TMD) is a highly conserved, hydrophobic alpha-helical segment that anchors the Env glycoprotein complex into the viral lipid bilayer [UniProt P04578]. Beyond its structural role as an anchor, the TMD is a dynamic participant in the viral entry process, facilitating the merger of viral and host cell membranes by stabilizing the fusion pore and communicating conformational changes from the extracellular domains [PMID: 27054313]. During the fusion process, the TMD interacts with the fusion peptide and the heptad repeat regions (HR1 and HR2) to transition the gp41 subunit into a six-helix bundle, a state essential for membrane apposition and viral entry [PMID: 17003040]. In the context of disease, the gp41 TMD is indispensable for HIV-1 infectivity, as it ensures the successful delivery of the viral genome into the host cell cytoplasm [PMID: 27054313]. While current clinical fusion inhibitors like Enfuvirtide primarily target the extracellular HR1 region of gp41, the TMD is increasingly recognized as a viable target for next-generation therapeutics, including small molecules and peptides designed to disrupt the late stages of membrane fusion [PMID: 30254001]. Mutations within this domain can significantly impact viral fitness and sensitivity to neutralization, highlighting its importance in drug resistance and vaccine design [PMID: 27054313].

Other names

gp41 TM domainHIV-1 gp41 transmembrane regionTransmembrane glycoprotein gp41 TMDgp41 TMD

Inhibition of viral-host membrane fusion by preventing the formation of the six-helix bundle or disrupting the stability of the transmembrane anchor during the fusion process [PMID: 27054313, DrugBank DB00102].