FEBS Letters · 2012 · 87 citations · 19 references
Life SciencesBiochemistryMolecular BiologyMolecular OncologyOncogenesStructural BiologyEnzyme FunctionLigand BindingMacromolecular AssemblyProtein StructureRas Family OncogenesSmall Gtpase SignalingOncogenic Ras MutationsRas Conformational StatesRas Gtpase SignalingRas SignalingRas Structure-function RelationshipsSide PocketsSubstrate Binding PocketsWild-type Ras Function
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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