Gp41 of HIV1

Human immunodeficiency virus 1 (HIV-1) is the causative pathogen of acquired immunodeficiency syndrome (AIDS). The precursor protein gp160 is cleaved into gp120, the receptor-binding protein, and gp41, the fusion protein. In contrast to HA, the association of the gp120/gp41 complex is noncovalent. The resulting protein complex, also referred to as Env protein, is composed of three gp120 and three gp41 subunits and is exposed at the surface of the virus. Recognition of CD4

receptors present on T-cells, macrophages, and monocytes by gp120 induces a first conformational change and enables binding of co-receptors, particularly chemokine receptors CCR5 and CXCR4. A second conformational change then leads to the release of gp41, which is sufficient for catalyzing membrane fusion. On the contrary to HA, no change in pH or temperature is required for activation of the fusion protein. Though no structure of the pre-fusion state of gp41 is available to date, the structural similarity of the recombinantly expressed ectodomain of gp41 with the post-fusion state of HA2 suggests that the sequence of events leading to membrane fusion is similar for the two proteins (Chan et al. 1997; Tan et al. 1997; Weissenhorn et al. 1997). As detailed above (see Sect. 3.1), the structure of the fusion protein reveals a six-helix bundle containing in its center a trimeric coiled-coil stalk of HR1 immediately C-terminal to the fusion peptide. Three HR2 helices pack into the hydrophobic grooves formed by the HR1 trimer, which accommodate three hydrophobic amino acid residues of HR2, that is, W628, W631, and I635 (numbers refer to the precursor gp160).

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