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Updated: Jan 8, 2026

Spatio-Temporal Manipulation of Small GTPase Activity at Subcellular Level and on Timescale of Seconds in Living Cells
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Spatio-Temporal Manipulation of Small GTPase Activity at Subcellular Level and on Timescale of Seconds in Living Cells

Published on: March 9, 2012

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

Carsten Kötting1,2, Till Rudack3,4,5, Klaus Gerwert1,2

  • 1Center for Protein Diagnostics (PRODI), Biospectroscopy, Ruhr University Bochum, Bochum, Germany.

Biological Chemistry
|December 19, 2025
PubMed

Insights

Ras, a key regulator of cell signaling, is implicated in many cancers. This review details Ras-catalyzed GTP hydrolysis mechanisms, focusing on conformational dynamics and key residues involved in turning off Ras signaling.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Ras proteins are crucial regulators of intracellular signal transduction pathways.
  • Dysregulation of Ras signaling is frequently observed in various oncological diseases.
  • Ras activity is controlled by the hydrolysis of bound GTP, a process facilitated by GTPase-activating proteins (GAPs).

Purpose of the Study:

  • To elucidate the intricate mechanism of Ras-catalyzed GTP hydrolysis.
  • To highlight the role of conformational dynamics and catalytic mechanisms in Ras regulation.
  • To review recent advancements in Ras-targeting drug development.

Main Methods:

  • Structural analysis of Ras proteins using X-ray crystallography.
  • Investigation of reaction dynamics via time-resolved FTIR spectroscopy.
  • Computational modeling through hybrid quantum mechanics/molecular mechanics (QM/MM) calculations.

Main Results:

  • Detailed reaction mechanisms, including arginine finger involvement and phosphate release, have been elucidated.
  • Key residues such as Thr35, Gly60, Tyr32, Gln61, Gly12, and Gly13 play critical roles in catalysis.
  • Recent findings support a solvent-assisted pathway for Ras GTP hydrolysis.

Conclusions:

  • Understanding Ras GTP hydrolysis is vital for comprehending its role in cancer.
  • Structural and dynamic insights provide a basis for developing novel Ras-targeting therapies.
  • Continued research into Ras signaling mechanisms promises new avenues for cancer treatment.
Keywords:
FTIR-spectroscopyGTPaseQM/MM calculationsRasX-ray crystallography

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