title: Crystal structures of the state 1 conformations of the GTP-bound H-Ras protein and its oncogenic G12V and Q61L mutants.
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.
authors.affiliation: Division of Molecular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Muraoka
authors.forename: Fumi
authors.initials: F
authors.lastname: Shima
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Araki
authors.forename: Tomoko
authors.initials: T
authors.lastname: Inoue
authors.forename: Akiko
authors.initials: A
authors.lastname: Yoshimoto
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ijiri
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Seki
authors.forename: Atsuo
authors.initials: A
authors.lastname: Tamura
authors.forename: Takashi
authors.initials: T
authors.lastname: Kumasaka
authors.forename: Masaki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Tohru
authors.initials: T
authors.lastname: Kataoka
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D006160:Guanosine Triphosphate / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D020125:Mutation, Missense; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016283:Proto-Oncogene Proteins p21(ras) / Q000737:chemistry* / Q000235:genetics
chemical_list: D006160:Guanosine Triphosphate; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)