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Crystal structures of the state 1 conformations of the GTP‐bound H‐Ras protein and its oncogenic G12V and Q61L mutants
Author(s) -
Muraoka Shin,
Shima Fumi,
Araki Mitsugu,
Inoue Tomoko,
Yoshimoto Akiko,
Ijiri Yuichi,
Seki Nobuaki,
Tamura Atsuo,
Kumasaka Takashi,
Yamamoto Masaki,
Kataoka Tohru
Publication year - 2012
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2012.04.058
Subject(s) - gtp' , gtpase , mutant , wild type , chemistry , small gtpase , crystallography , mutation , crystal structure , stereochemistry , enzyme , gene , biochemistry , signal transduction
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.