Background: The envelope glycoprotein of the human (HIV) and related simian (SIV) immunodeficiency virus are synthesized as gp160 precursors which are processed into two non-covalently associated glycoproteins: gp120 and gp41. The gp120 mediates viral entry into the host cell by binding to the cellular receptor CD4 and a chemokine coreceptor, both of which are located on the host cell surface. This binding induces conformational changes in the transmembrane gp41, which facilitates membrane fusion between the viral and host membranes. An understanding of these processes at the molecular level may lead to a direct means of inhibiting HIV infection. HIV pg41, and the closely related SIV gp41, are heavily glycosylated transmembrane proteins. The ectodomain region, located on the outer surface of the viral membrane directly mediates membrane fusion events via an N-terminal fusion domain. Both the NMR and X-ray structures of the gp41 ectodomain have been solved. The structure determined by both methods is a rod-like trimer comprising three parallel N-terminal alpha-helices assembled as a coiled-coil in the center with three antiparallel C-terminal alpha-helices packed on the outside with highly flexible loops connecting the inner and outer helices. Results: To gain further insight into gp41 function we have expressed in bacteria regions of the protein for which there is currently no structural information, namely, the extremely hydrophobic N-terminal fusion peptide, the transmembrane region and the long cytoplasmic domain. The proteins produced are being studied by new NMR techniques (A. Bax) designed for the structural analysis of membrane proteins and peptides. The structure of a membrane associated region of the cytoplasmic domain has been determined. The helical structure determined has a pronounced amphiphatic character, with Lue and Trp defining the hydrophobic surface associated with lipid. The structure of the N-terminal fusion domain is currently under study. In other studies we are continuing to produce regions of the HIV gp41 ectodomain in order to raise antibodies against potential receptor-activated conformations. Significance and future direction: More detailed structure determinations of the whole gp41 protein will allow a more rational approach to the design of novel peptide inhibitors.
| Jaroniec, Christopher P; Kaufman, Joshua D; Stahl, Stephen J et al. (2005) Structure and dynamics of micelle-associated human immunodeficiency virus gp41 fusion domain. Biochemistry 44:16167-80 |
| Desmezieres, Emmanuel; Gupta, Nidhi; Vassell, Russell et al. (2005) Human immunodeficiency virus (HIV) gp41 escape mutants: cross-resistance to peptide inhibitors of HIV fusion and altered receptor activation of gp120. J Virol 79:4774-81 |
| Chou, James J; Kaufman, Joshua D; Stahl, Stephen J et al. (2002) Micelle-induced curvature in a water-insoluble HIV-1 Env peptide revealed by NMR dipolar coupling measurement in stretched polyacrylamide gel. J Am Chem Soc 124:2450-1 |
