The overall objective is to provide a structural basis for understanding how certain tumors are caused by ras oncogene products. The specific objective of this proposal is to determine the 3dimensional structures of three classes of ras oncogene products, K-, H, and Nras proteins, by Xray diffraction methods. In each class there are three types of proteins: viral, normal cellular, and activated cellular ras proteins. These structures may (a) provide a basis for understanding the biochemical differences between normal and activated cellular ras gene products; (b) suggest other functional roles (including the normal cellular functions) of the ras proteins; (c) reveal the possible conformational changes on guanine nucleotide binding; and (d) lay a foundation for rational designing of the ligands that could modulate known biochemical functions of the ras proteins.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA045593-03
Application #
3188715
Study Section
Biophysics and Biophysical Chemistry A Study Section (BBCA)
Project Start
1987-08-01
Project End
1992-06-30
Budget Start
1989-09-01
Budget End
1990-07-31
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Type
Schools of Arts and Sciences
DUNS #
094878337
City
Berkeley
State
CA
Country
United States
Zip Code
94704
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Langen, R; Schweins, T; Warshel, A (1992) On the mechanism of guanosine triphosphate hydrolysis in ras p21 proteins. Biochemistry 31:8691-6
Prive, G G; Milburn, M V; Tong, L et al. (1992) X-ray crystal structures of transforming p21 ras mutants suggest a transition-state stabilization mechanism for GTP hydrolysis. Proc Natl Acad Sci U S A 89:3649-53
Tong, L A; de Vos, A M; Milburn, M V et al. (1991) Crystal structures at 2.2 A resolution of the catalytic domains of normal ras protein and an oncogenic mutant complexed with GDP. J Mol Biol 217:503-16
Milburn, M V; Tong, L; deVos, A M et al. (1990) Molecular switch for signal transduction: structural differences between active and inactive forms of protooncogenic ras proteins. Science 247:939-45
Brunger, A T; Milburn, M V; Tong, L et al. (1990) Crystal structure of an active form of RAS protein, a complex of a GTP analog and the HRAS p21 catalytic domain. Proc Natl Acad Sci U S A 87:4849-53
Rine, J; Kim, S H (1990) A role for isoprenoid lipids in the localization and function of an oncoprotein. New Biol 2:219-26
Schafer, W R; Kim, R; Sterne, R et al. (1989) Genetic and pharmacological suppression of oncogenic mutations in ras genes of yeast and humans. Science 245:379-85
Holbrook, S R; Kim, S H (1989) Molecular model of the G protein alpha subunit based on the crystal structure of the HRAS protein. Proc Natl Acad Sci U S A 86:1751-5
de Vos, A M; Tong, L; Milburn, M V et al. (1988) Three-dimensional structure of an oncogene protein: catalytic domain of human c-H-ras p21. Science 239:888-93

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