Why have mutagenesis studies not located the general base in ras p21

Nat Struct Biol. 1994 Jul;1(7):476-84. doi: 10.1038/nsb0794-476.


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 Ras 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 GTP 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 GTP itself. Obviously, the identification of such a general base cannot be easily accomplished by mutagenesis experiments.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Binding Sites
  • Computer Simulation*
  • Genes, ras
  • Guanosine Triphosphate / chemistry*
  • Guanosine Triphosphate / physiology
  • Humans
  • Hydrolysis
  • Models, Chemical
  • Models, Molecular*
  • Mutagenesis, Site-Directed*
  • Protein Conformation*
  • Proto-Oncogene Proteins p21(ras) / chemistry*
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Thermodynamics
  • Water / chemistry


  • Water
  • Guanosine Triphosphate
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)