Related Experiment Video

Updated: Oct 26, 2025

Single-Molecule FRET Imaging for Observing the Conformational Dynamics of Dynamin-Like GTPase Atlastin
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Single-Molecule FRET Imaging for Observing the Conformational Dynamics of Dynamin-Like GTPase Atlastin

Published on: January 24, 2025

722

Conformational Features of Ras: Key Hydrogen-Bonding Interactions of Gln61 in the Intermediate State during GTP

Juan Zeng1, Jingwei Weng2, Yuwei Zhang3

  • 1School of Biomedical Engineering, Guangdong Medical University, Dongguan 523808, China.

The Journal of Physical Chemistry. B
|July 29, 2021
PubMed

Insights

Novel drug design for Ras cancer targets is advanced by characterizing RasGDP·Pi and RasGDP states. Unrecognized hydrogen bonds stabilize the intermediate, offering new therapeutic strategies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Ras protein is a critical target for cancer drug development.
  • Understanding Ras conformational states is key for designing effective therapeutics.

Purpose of the Study:

  • To characterize the conformational ensembles of RasGDP·Pi and RasGDP.
  • To identify novel stabilization or disruption strategies for Ras-targeted cancer therapies.

Main Methods:

  • Extensive replica-exchange molecular dynamics simulations were employed.
  • Structural analyses identified key hydrogen-bonding networks and conformational substates.

Main Results:

  • Several substates for the RasGDP·Pi hydrolysis intermediate were identified.
  • An unrecognized hydrogen-bonding network was discovered, stabilizing the RasGDP·Pi state.
  • Gln61, implicated in oncogenic mutations, adopts a specific conformation in RasGDP·Pi.
  • RasGDP exhibits multiple substates, suggesting a conformational selection mechanism for GEF interactions.

Conclusions:

  • Findings provide new opportunities for Ras-targeted cancer drug design.
  • Strategies include stabilizing the RasGDP·Pi intermediate or disrupting Ras-GEF interactions.

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