This proposal focuses on a recently described structural motif, called the """"""""leucine zipper"""""""", that is found in some DNA binding proteins. The long-term objectives of the proposed research are to understand the relationship between structure and function in leucine zippers, and to understand how this new class of proteins bind DNA in a sequence specific manner. The proposed research is significant for understanding protein-DNA interactions, specific protein-protein interactions, transcriptional activation, and oncogenesis.
The specific aims of the research are: (1) to determine the structure of a synthetic peptide corresponding to the leucine zipper region of a yeast transcriptional activator called GCN4, using crystallography (in collaboration with a crystallographer) and 2D-NMR methods; (2) to determine how a 60-residue fragment of GCN4, that includes the leucine zipper, is capable of binding DNA in a sequence-specific manner, using 2D-NMR and mutagenesis studies: and (3) to determine the mechanism for specific heterodimer formation by two leucine zipper peptides that correspond to regions of the nuclear oncogene products Fos and Jun, using structural studies and synthesis of variant peptides.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM044162-05
Application #
2182401
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Project Start
1990-04-01
Project End
1995-03-31
Budget Start
1994-04-01
Budget End
1995-03-31
Support Year
5
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
076580745
City
Cambridge
State
MA
Country
United States
Zip Code
02142
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
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
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
Keating, A E; Malashkevich, V N; Tidor, B et al. (2001) Side-chain repacking calculations for predicting structures and stabilities of heterodimeric coiled coils. Proc Natl Acad Sci U S A 98:14825-30
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

Showing the most recent 10 out of 26 publications