HIV-1 envelope glycoprotein gp41 (gp41)

HIV-1 envelope glycoprotein gp41 is a 345 amino acid transmembrane protein that plays a critical role in HIV-1 viral entry into host cells[3][4]. It can be segmented into three domains: an exposed ectodomain (amino acids 1-172), a transmembrane domain, and a cytoplasmic tail (CT) region (amino acids 195-345)[4]. The structure of gp41 is complex and undergoes significant conformational changes during the viral fusion process. In a free virion, the fusion peptides at the amino termini of gp41 are buried within the envelope complex in an inactive non-fusogenic state that is stabilized by a non-covalent bond with gp120[3]. When gp120 binds to CD4 and a co-receptor (CCR5 or CXCR4) on susceptible cells like Helper T cells and macrophages, it triggers a cascade of conformational changes in both gp120 and gp41 proteins[3]. Key structural elements of gp41 include: 1. **Fusion Peptide (FP)**: Highly conserved (84%) and involved in interaction with fusion inhibitors like T-20[4]. 2. **N-terminal Heptad Repeat (N-HR)**: Forms part of the six-helix bundle structure during fusion, highly conserved (86.2%)[4][5]. 3. **Fusion Peptide Proximal Region (FPPR)**: Well-conserved domain (84.9%) also implicated in interaction with fusion inhibitors[4]. 4. **Membrane-Proximal External Region (MPER)**: Highly conserved (84.2%) and plays a role in membrane fusion[1][4][5]. 5. **Transmembrane Domain (TMD)**: Forms an α-helical structure in membrane-mimicking environments and shows conformational flexibility[1][6]. 6. **Cytoplasmic Tail (CT)**: The least conserved domain despite its important role in envelope conformation and incorporation into budding viral particles[4]. During the fusion process, gp41 refolds into a six-helix bundle structure, bringing the viral and cellular membranes into close proximity[5][6]. This refolding process involves a coiled coil-to-lipid-embedded helix transition in MPER and reorientation of the C-terminal ectodomain[5]. The structure is cage-like with a hollow center that inhibits antibody access[3]. The trimerization specificity of native gp41 may reside in the MPER segment abutting the transmembrane anchor[5]. High-resolution NMR data has confirmed that the C-terminal segment of MPER and the TMD adopt α-helical structures in membrane-mimicking environments, with conformational flexibility around the transmembrane sequence[1].

Other names

Transmembrane glycoprotein gp41HIV-1 transmembrane envelope proteingp41 ectodomainHIV-1 gp41 transmembrane domain (TMD)

Fusion inhibition (T-20 prevents the virus from entering the cell by binding to gp41 domains)