Structural changes induced in p21(Ras) upon GAP-334 complexation as probedby ESEEM spectroscopy and molecular-dynamics simulation

Background: The means by which the protein GAP accelerates GTP hydrolysis, and thereby downregulates growth signaling by p21(Ras), is of considerable interest, particularly inasmuch as p21 mutants are implicated in a number o f human cancers. A GAP "arginine finger," identified by X-ray crystallograp hy, has been suggested as playing the principal role in the GTP hydrolysis. Mutagenesis studies, however, have shown that the arginine can only partia lly account far the 10(5)-fold increase in the GAP-accelerated GTPase rate of p21.