The Ras-RasGAP complex: How to complement an inefficient active site

GTP-hydrolysis as carried out by GTP-binding proteins([1]) is intrinsically very slow but can be accelerated by orders of magnitude upon interaction w ith GTPase Activating Proteins, GAPs, which are specific for the respective GTP-binding proteins. Focusing on p21ras (Ras), a key element in growth co ntrol and differentiation, we have used biochemical and structural methods to elucidate the mechanism of GTPase activation. An arginine side chain is supplied into the active site of Ras to contact the nucleotide and stabiliz e the transition state of the reaction, consistent with mutational analyses . The switch II region of Ras is stabilized by GAP-334 to allow Gln61, the mutation of which activates the oncogenic potential of Ras, to participate in catalysis. The structure provides an explanation how Gly12 and Gln61 mut ations might escape regulation by GAPs.