The central objective of this proposal is to contribute to the development of an understanding of the physical basis for protein-protein interactions. Coiled-coils are the subject of the proposal, which has a particular emphasis on the structural determinants of homodimer and heterodimer formation amongst this important and common class of protein-protein complexes. An array of techniques is to be employed including x-ray crystallography, computational methods, thermodynamic analysis and genetic screens. The proposal seeks to characterize the role of buried polar interactions in delineating the specificity of coiled-coil interactions; to extend a recently developed computational algorithm for sidechain repacking in an effort to efficiently explore the parameters that affect the thermodynamics of partnering; to undertake a database analysis of sequence determinants of partnering with an ultimate aim of developing algorithms that will faithfully reveal such interactions; and to test and extend existing knowledge about coiled-coil interactions by analyzing partnering at a genomic level using a yeast-based experimental system.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular and Cellular Biophysics Study Section (BBCA)
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Wehrle, Janna P
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Whitehead Institute for Biomedical Research
United States
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Sia, Samuel K; Carr, Peter A; Cochran, Andrea G et al. (2002) Short constrained peptides that inhibit HIV-1 entry. Proc Natl Acad Sci U S A 99:14664-9
Sia, S K; Kim, P S (2001) A designed protein with packing between left-handed and right-handed helices. Biochemistry 40:8981-9
Chen, B K; Rousso, I; Shim, S et al. (2001) Efficient assembly of an HIV-1/MLV Gag-chimeric virus in murine cells. Proc Natl Acad Sci U S A 98:15239-44
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Akey, D L; Malashkevich, V N; Kim, P S (2001) Buried polar residues in coiled-coil interfaces. Biochemistry 40:6352-60
Eckert, D M; Kim, P S (2001) Design of potent inhibitors of HIV-1 entry from the gp41 N-peptide region. Proc Natl Acad Sci U S A 98:11187-92
Newman, J R; Wolf, E; Kim, P S (2000) A computationally directed screen identifying interacting coiled coils from Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 97:13203-8
Zhao, X; Singh, M; Malashkevich, V N et al. (2000) Structural characterization of the human respiratory syncytial virus fusion protein core. Proc Natl Acad Sci U S A 97:14172-7
Singh, M; Berger, B; Kim, P S (1999) LearnCoil-VMF: computational evidence for coiled-coil-like motifs in many viral membrane-fusion proteins. J Mol Biol 290:1031-41
Oakley, M G; Kim, P S (1998) A buried polar interaction can direct the relative orientation of helices in a coiled coil. Biochemistry 37:12603-10

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