gp4l plays a central role in HIV infection by initiating the fusion of the viral and target cell membranes, thereby allowing the viral core particle to enter the cytoplasm of the target cell. Therapies designed to disrupt gp4l function are especially attractive for the prevention and treatment of AIDS patients because of their potential prophylactic properties, as well as being alternative and complementary therapies to the protease and reverse transcriptase inhibitors currently employed. Recently, structural information has become available for regions of the gp4l and gp120 in isolation; however, there is no structural information for the gp41/gp120 complex. Furthermore, there are significant gaps in our knowledge concerning the molecular basis for gp41-mediated membrane fusion and the mechanism of peptide inhibition of gp4l function. The long term goal of this proposal is to relate the structural properties of gp4l to its functional properties, which could serve as the basis for the design of new therapies for the prevention and treatment of AIDS. The general hypotheses are that: (i) the loop region of the gp4l ectodomain interacts with the C1 and C5 domains of gp120 while gp4l is in a compact conformation; (ii) peptide inhibitors of HIV infection bind to the compact form of gp41.
The specific aims are: 1) determination of the structure and dynamic properties of the HIV gp4l ectodomain; 2) elucidation of the mechanism of gp4l peptide inhibition of HIV infection; 3) development of a site-directed mutagenesis system to relate HIV gp4l structure to function. In this proposal, a combined approach of molecular biology, biochemistry and NMR spectroscopy will be employed.
| Sen, Jayita; Yan, Tianran; Wang, Jizhen et al. (2010) Alanine scanning mutagenesis of HIV-1 gp41 heptad repeat 1: insight into the gp120-gp41 interaction. Biochemistry 49:5057-65 |
| McReynolds, Susanna; Jiang, Shaokai; Rong, Lijun et al. (2009) Dynamics of SARS-coronavirus HR2 domain in the prefusion and transition states. J Magn Reson 201:218-21 |
| Guo, Ying; Tisoncik, Jennifer; McReynolds, Susanna et al. (2009) Identification of a new region of SARS-CoV S protein critical for viral entry. J Mol Biol 394:600-5 |
| Sen, Jayita; Jacobs, Amy; Caffrey, Michael (2008) Role of the HIV gp120 conserved domain 5 in processing and viral entry. Biochemistry 47:7788-95 |
| Wang, Jizhen; Sen, Jayita; Rong, Lijun et al. (2008) Role of the HIV gp120 conserved domain 1 in processing and viral entry. J Biol Chem 283:32644-9 |
| Sen, Jayita; Jacobs, Amy; Jiang, Haiqing et al. (2007) The disulfide loop of gp41 is critical to the furin recognition site of HIV gp160. Protein Sci 16:1236-41 |
| Jacobs, Amy; Simon, Cecile; Caffrey, Michael (2006) Thermostability of the HIV gp41 wild-type and loop mutations. Protein Pept Lett 13:477-80 |
| Jacobs, Amy; Sen, Jayita; Rong, Lijun et al. (2005) Alanine scanning mutants of the HIV gp41 loop. J Biol Chem 280:27284-8 |
| Jacobs, Amy; Hartman, Kari; Laue, Thomas et al. (2004) Sedimentation velocity studies of the high-molecular weight aggregates of the HIV gp41 ectodomain. Protein Sci 13:2811-3 |
| Guilhaudis, Laure; Jacobs, Amy; Caffrey, Michael (2002) Solution structure of the HIV gp120 C5 domain. Eur J Biochem 269:4860-7 |
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