Crystal structures of the state 1 conformations of the GTP-bound H-Ras protein and its oncogenic G12V and Q61L mutants

FEBS Letters
Shin MuraokaTohru Kataoka

Abstract

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 γ-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.

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Citations

May 1, 2013·Proceedings of the National Academy of Sciences of the United States of America·Fumi ShimaTohru Kataoka
Jun 16, 2014·Nature Chemical Biology·Jochen SpiegelHerbert Waldmann
Jun 6, 2013·Proceedings of the National Academy of Sciences of the United States of America·Harrison J HockerAlemayehu A Gorfe
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May 23, 2020·The Journal of Physical Chemistry. B·Van A NgoAngel E Garcia

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