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Updated: Dec 23, 2025

Visualizing the Conformational Dynamics of Membrane Receptors Using Single-Molecule FRET
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NMR-Derived Conformational Ensemble of State 1 of Activated Ras Reveals Insights into a Druggable Pocket

Dan Liu1, Xiaomin Chen1, Dong Long1,2

  • 1Hefei National Laboratory for Physical Sciences at the Microscale, MOE Key Laboratory for Membraneless Organelles & Cellular Dynamics, School of Life Sciences, University of Science and Technology of China, Hefei 230027, China.

The Journal of Physical Chemistry Letters
|April 18, 2020
PubMed

Insights

Designing drugs against Ras oncogenic protein is challenging. A new study reveals a flexible, druggable pocket in Ras state 1, aiding rational drug design for anti-Ras therapies.

Area of Science:

  • Oncogenic signaling pathways
  • Structural biology
  • Drug discovery

Background:

  • Ras proteins are key oncogenic drivers, but their lack of defined pockets hinders inhibitor design.
  • The transiently formed state 1 of activated Ras presents a potential, albeit flexible, drug target.

Purpose of the Study:

  • To characterize the conformational landscape of Ras state 1.
  • To identify and analyze druggable pockets within this flexible state.
  • To provide structural templates for rational anti-Ras drug design.

Main Methods:

  • Utilized chemical shift-based modeling to generate a conformational ensemble of Ras state 1.
  • Analyzed the ensemble to reveal intrinsic pocket plasticity.
  • Investigated the mechanism of conformational selection in inhibitor recognition.

Main Results:

  • Developed a comprehensive conformational ensemble for Ras state 1, capturing its dynamic nature.
  • Identified a druggable pocket with significant plasticity within the ensemble.
  • Demonstrated how inhibitor recognition is mediated by conformational selection.

Conclusions:

  • The conformational ensemble of Ras state 1 offers a detailed view of accessible pocket conformations.
  • This plasticity and mechanism of selection are crucial for designing effective anti-Ras drugs.
  • The findings are expected to significantly advance rational drug discovery efforts targeting Ras.

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