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

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• 作者：Shin Muraoka^a ; ¹ ; Fumi Shima^a ; ¹ ; Mitsugu Araki^b ; Tomoko Inoue^a ; Akiko Yoshimoto^a ; Yuichi Ijiri^a ; Nobuaki Seki^b ; Atsuo Tamura^b ; Takashi Kumasaka^c ; Masaki Yamamoto^d ; Tohru Kataoka^a ; ^{kataoka@people.kobe-u.ac.ip}
• 关键词：GAP ; GTPase-activating protein ; GppNHp ; guanosine 5&prime ; -(¦Â ; ¦Ã-imido)triphosphate ; RBD ; Ras-binding domain ; WT ; Wild type ; rms ; root mean square
• 出版年：2012
• 出版时间：12 June, 2012
• 年：2012
• 卷：586
• 期：12
• 页码：1715-1718
• 全文大小：645 K

文摘

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 ¦Ã-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.