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Crystal Packing Reveals a Potential Autoinhibited KRAS Dimer Interface and a Strategy for Small-Molecule Inhibition

Robert J Brenner1, Alexander D Landgraf1, Khuchtumur Bum-Erdene1

  • 1Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States.

Biochemistry
|November 8, 2023
PubMed

Insights

Researchers discovered a novel KRAS G12D protein structure that forms a druggable interface. This finding offers a new strategy for inhibiting RAS signaling in cancer by targeting this autoinhibited conformation.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Oncology

Background:

  • KRAS GTPases are frequently mutated in human cancers, driving tumor growth.
  • KRAS is notoriously difficult to drug due to the absence of a clear small-molecule binding site.

Purpose of the Study:

  • To investigate the structural basis of KRAS G12D.
  • To identify potential druggable sites on KRAS for cancer therapy.

Main Methods:

  • X-ray crystallography of His-tagged KRAS G12D.
  • Alanine-scanning mutagenesis.
  • Alchemical free energy perturbation calculations.
  • Explicit-solvent molecular dynamics simulations.

Main Results:

  • A unique crystal structure revealed a KRAS G12D conformational change forming a protein-protein-like interface.
  • Key interface amino acids were identified as hot spots contributing significantly to the interaction.
  • Computational analysis identified two large, druggable pockets within the complex structure.

Conclusions:

  • The identified interface and pockets represent a novel, potentially druggable conformation of KRAS.
  • Targeting this autoinhibited KRAS structure may offer a new therapeutic strategy for cancers with KRAS mutations.

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