Phosphoryl transfer in Ras proteins, conclusive or elusive?

The chemical mechanism of GTP hydrolysis by GTP-binding proteins of the Ras superfamily continues to inspire both experimental and computational biologists. The debate centres on the nature of the transition state, with arguments for both dissociative and associative, and whether there is a common GTPase mechanism for these proteins. In a recent structural analysis of Rab11, the product P-i was found in an unusual configuration. This finding indicates that substrate-assisted catalysis might operate as a mechanism to enable nucleophilic attack in the intrinsic GTPase reaction, and would thus favour a pentavalent phosphorane intermediate. Recent findings on the GAP-mediated reaction of different Ras proteins suggest that a common mechanism might not exist and that G proteins probably show a continuum of electronic configurations in the transition state.