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Updated: Aug 25, 2025

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The dynamicity of mutant KRAS β2 strand modulates its downstream activation and predicts anticancer KRAS inhibition

Jeiran Pashapour Anousheh1, Abolfazl Barzegar2, Mohammad Saeid Hejazi1

  • 1Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.

Life Sciences
|October 13, 2022
PubMed
Abstract

Insights

KRAS mutations drive cancer. This study reveals KRAS beta2-strand length as a key indicator of KRAS activity, even for mutants, aiding targeted cancer therapy development.

Area of Science:

  • Molecular biology
  • Biochemistry
  • Structural biology

Background:

  • KRAS mutations are primary drivers in human cancers.
  • Understanding KRAS conformational states is crucial for targeted therapies.

Purpose of the Study:

  • To identify specific conformational features of active KRAS.
  • To investigate these features in mutant KRAS forms and their impact on signaling.

Main Methods:

  • Employed Molecular Dynamics (MD) simulations and post-MD analyses.
  • Utilized clustering, umbrella sampling, and principal component analysis.
  • Assessed conformations via beta2-strand length, residue distances, and interactions.

Main Results:

  • KRAS beta2-strand length (9-10 residues) correlates with active conformations.
  • KRAS G12 mutants in GDP-bound states can exhibit active conformations due to longer beta2-strands.
  • The E37-A59 residue distance also indicates KRAS activity.
  • Beta2-strand length predicts KRAS activity even with direct inhibitors.

Conclusions:

  • Provides a novel mechanism for KRAS-GDP direct inhibition efficacy in cancer.
  • Beta2-strand length probability facilitates the design and screening of mutant KRAS inhibitors.
Keywords:
Beta-sheetDownstream signalingKRASMD simulationProtein structure

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