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 in molecular detail may lead to directed and novel means of inhibiting HIV infection. Using bacterial expression systems we have produced regions of the transmembrane SIV and HIV gp41 proteins normally located on the outer surface of the viral membrane (termed ectodomains). These proteins have been extensively studied by biophysical methods, X-ray crystallography (Hyde) and NMR (Clore). A low resolution NMR structure of the SIV gp41 (residues 27-149) indicates a trimeric coiled-coil structure with a partially ordered loop region clustered at one end of the structure. This important loop structure is the immunodominant domain of the gp41 protein (antibodies against this surface exposed epitope are demonstrable at most stages of HIV infection). The X-ray structure determination of the SIV gp41 protein is nearing completion and we recently have succeeded in obtaining crystals of the HIV gp41. We are currently attempting to express other regions of the gp41 protein, including the transmembrane region. We are making these proteins as novel fusion proteins to aid in their solubilization and handling. The structural analysis of these larger proteins may provide additional insight into the structure-function relationships of gp41.
| 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 |
