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Comparing the Affinity of GTPase-binding Proteins using Competition Assays
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Recent breakthroughs in understanding the allosteric features of Ras GTPases and their effector and regulatory

Nisha Bhattarai1, Matthias Buck2

  • 1Department of Physiology & Biophysics, Case Western Reserve University, Cleveland, OH 44106, USA.

Current Opinion in Structural Biology
|December 16, 2025
PubMed

Insights

Targeting Ras GTPase proteins, mutated in many cancers, is advancing rapidly. Recent progress in drug discovery for these previously undruggable targets is reviewed, highlighting new insights into Ras conformational dynamics and interactions.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Ras guanosine triphosphate hydrolases (GTPases) are crucial in cell signaling.
  • Mutations in Ras GTPases are implicated in driving numerous cancers.
  • Ras proteins were historically considered undruggable targets for cancer therapy.

Purpose of the Study:

  • To review recent advancements in Ras-targeted drug discovery.
  • To highlight the role of understanding Ras conformational changes and interactions in this progress.
  • To discuss developments concerning GTPase-activating proteins (GAP) and effector proteins.

Main Methods:

  • Deep mutational scanning
  • Solution nuclear magnetic resonance (NMR) spectroscopy
  • Computational modeling and simulations

Main Results:

  • Significant progress has been made in designing and screening Ras-targeting drugs.
  • Detailed understanding of Ras conformational dynamics, sparse populations, and allosteric interactions is key.
  • Recent developments have also impacted studies on NF1, plexin, and Raf proteins.

Conclusions:

  • The past five years have seen dramatic progress in targeting Ras GTPases for cancer therapy.
  • Advanced techniques have elucidated critical aspects of Ras protein behavior.
  • Further research is needed to address existing gaps in understanding for comprehensive therapeutic strategies.

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