Related Experiment Video

Updated: Aug 16, 2025

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Exploring the state- and allele-specific conformational landscapes of Ras: understanding their respective

Hui Wang1, Dan Liu1, Yongkui Yu1

  • 1MOE Key Laboratory for Cellular Dynamics and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China. dlong@ustc.edu.cn.

Physical Chemistry Chemical Physics : PCCP
|December 20, 2022
PubMed

Insights

Ras protein dynamics reveal vulnerable pockets for cancer drug development. Understanding these conformational changes is key for creating effective, allele-specific Ras inhibitors.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Pharmacology

Background:

  • Ras proteins are key regulators of cell signaling, and their mutations are major drivers of cancer.
  • Targeting Ras directly is challenging due to its dynamic nature and the need for allele-specific strategies.
  • The impact of oncogenic mutations and activation states on Ras dynamics and drug accessibility remains poorly understood.

Purpose of the Study:

  • To characterize how nucleotide state and specific mutations alter Ras protein dynamics.
  • To investigate the free energy landscape governing Ras conformational changes and druggability.
  • To identify mechanisms affecting the accessibility of cryptic pockets for inhibitor binding.

Main Methods:

  • Utilized a combination of Nuclear Magnetic Resonance (NMR) experiments and computational approaches.
  • Constructed quantitative ensembles to model Ras conformational dynamics.
  • Analyzed the accessibility of cryptic pockets (SI/II-P and SII-P) in different Ras states and mutants.

Main Results:

  • Identified conserved cryptic pockets (SI/II-P and SII-P) across different Ras states and alleles.
  • Revealed that local conformational changes reduce the accessibility of the SII-P pocket, particularly for Ras·GTP and Ras(G12D)·GDP.
  • Observed low reactivity of these Ras forms with covalent SII-P inhibitors due to impaired pocket accessibility.

Conclusions:

  • Ras dynamics are altered by nucleotide state and mutations, influencing inhibitor binding.
  • Conformational selection is a likely mechanism for Ras-binder interactions.
  • Findings provide insights for developing state- and allele-specific, as well as pan-Ras, inhibitors.

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