The long-term objective of this research plan is to establish the biophysical and structural basis of conformational changes in the membrane-spanning gp41 subunit of the HIV-1 envelope protein that mediates fusion of viral and cellular membranes. The focus is on the structure, folding and thermodynamics of a six-stranded helical bundle, located in the extracellular region (ectodomain) of gp41. This project will investigate the stability and specificity of coiled-coil interactions within the helical bundle, as well as the interaction between gp41 and the receptor-binding of gp120 subunit. The methodology involves dissection of the ectodomain of gp41 into modular subdomains that display essential features for biophysical and structural studies.
Specific aims of this research are: (1) To determine the biophysical and structural properties of the core subdomain of gp41, in order to understand the determinants for the formation of the fusion-active (fusogenic) conformation of gp41. (2) To evaluate the contributions of buried polar residues to the stability and conformational specificity in the core subdomain of gp41, in order to understand the native (nonfusogenic) structure of gp41. (3) To determine the structural basis for the interaction between the gp120 and gp41 subunits using peptide fragments, in order to understand the mechanism for regulating the conformation switch in gp41. Binding of gp120 to the cell-surface receptor CD4 results in conformational changes in the gp120/gp41 complex, leading to membrane fusion and virus entry. This project seeks to define both the native and fusogenic states of gp41, the nature of its conformational change, and the role of gp120 in controlling this structural rearrangement. As a result, this research will contribute to an increased understanding of HIV-1 membrane fusion process. This work also relates to aspects of protein-protein interactions and the protein folding process.
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| Horne, W Seth; Johnson, Lisa M; Ketas, Thomas J et al. (2009) Structural and biological mimicry of protein surface recognition by alpha/beta-peptide foldamers. Proc Natl Acad Sci U S A 106:14751-6 |
| Eggink, Dirk; Langedijk, Johannes P M; Bonvin, Alexandre M J J et al. (2009) Detailed mechanistic insights into HIV-1 sensitivity to three generations of fusion inhibitors. J Biol Chem 284:26941-50 |
