Structure-function correlation for ras p21 and the molecular origin of cancer

In the past five years the authors followed different routes in correlating the structure and function of p21{sup ras} on an atomic level. The main project focused on understanding the GTPase mechanism catalyzed by p21{sup ras} and other GTP-binding proteins. The progress on this front is summarized. The starting point was the crystal structure of p21{sup ras} that was solved by the Kim group and the Wittinghofer group and paved the way for any attempt of understanding the hydrolysis mechanism in this protein. The crystallographic analysis has identified a water molecule (Wat175) in a position that makes it likely to be able to act as the nucleophile in the hydrolysis reaction. This water is directly located between the {gamma}-phosphate and the side chain of Gln61 in one of its possible orientations. This arrangement and the fact that mutations of Gln61 decrease the GPTase reaction rate led to the suggestion that this residue plays an important role in catalysis by acting as the general base for the nucleophilic water molecule and that it is assisted by Glu63