WHY HAVE MUTAGENESIS STUDIES NOT LOCATED THE GENERAL BASE IN RAS P21

Ras p21 plays a major role in the control of cell growth, and oncogenic mutations of this protein have been found in human cancers. Unfortunately, the detailed mode of action of pas p21 is still unclear, in spite of the great interest in this protein and the availability of its X-ray crystal structure. In particular, mutagenesis studies of different active site residues could not identify the general base for GIP hydrolysis. Here we tackle this question using a computer simulation approach with clear and reliable energy considerations and conclude that the most likely general base is the bound CTP itself. Obviously, the identification of such a general base cannot be easily accomplished by mutagenesis experiments.