Mechanistic insights into Ras-catalyzed GTP hydrolysis: conformational dynamics, catalytic mechanisms, and emerging therapeutic strategies

Ras is a key regulator of signal transduction in cells. Ras malfunction is associated with a huge variety of oncological diseases. It is turned off by hydrolysis of bound GTP, which is accelerated by GTPase-activating proteins (GAPs). This minireview discusses the mechanism of Ras-catalyzed GTP hydrolysis, focusing on conformational dynamics and catalytic mechanisms. We discuss structural changes and the role of key residues such as Thr35, Gly60, Tyr32, Gln61, Gly12, and Gly13. Biophysical techniques such as X-ray crystallography, time-resolved FTIR spectroscopy, and hybrid quantum mechanics/molecular mechanics calculations have revealed the detailed reaction mechanisms, including the entry of the arginine finger and the rate-limiting step of inorganic phosphate release. Recent studies on the hydrolysis mechanism favor a solvent-assisted pathway. In addition, we summarize recent advances in Ras-targeting drugs.