Journal
FEBS LETTERS
Volume 586, Issue 12, Pages 1715-1718Publisher
WILEY
DOI: 10.1016/j.febslet.2012.04.058
Keywords
Ras; Small GTPases; Oncogene; Crystal structure; Conformational dynamics
Funding
- Ministry of Health, Labour and Welfare
- Ministry of Education, Science, Sports and Culture of Japan
- National Institute of Biomedical Innovation
- Grants-in-Aid for Scientific Research [10J00683, 23390071] Funding Source: KAKEN
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GTP-bound Ras adopts two interconverting conformations, inactive state 1 and active state 2. However, the tertiary structure of wild-type (WT) state 1 remains unsolved. Here we solve the state 1 crystal structures of H-Ras WT together with its oncogenic G12V and Q61L mutants. They assume open structures characterized by impaired interactions of both Thr-35 in switch I and Gly-60 in switch II with the gamma-phosphate of GTP and possess two surface pockets of mutually different shapes unseen in state 2, a potential target for selective inhibitor development. Furthermore, they provide a structural basis for the low GTPase activity of state 1. (c) 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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