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


ABSTRACT: KRAS GTPases harbor oncogenic mutations in more than 25% of human tumors. KRAS is considered to be largely undruggable due to the lack of a suitable small-molecule binding site. Here, we report a unique crystal structure of His-tagged KRASG12D that reveals a remarkable conformational change. The Switch I loop of one His-KRASG12D structure extends into the Switch I/II pocket of another His-KRASG12D in an adjacent unit cell to create an elaborate interface that is reminiscent of high-affinity protein-protein complexes. We explore the contributions of amino acids at this interface using alanine-scanning studies with alchemical free energy perturbation calculations based on explicit-solvent molecular dynamics simulations. Several interface amino acids were found to be hot spots as they contributed more than 1.5 kcal/mol to the protein-protein interaction. Computational analysis of the complex revealed the presence of two large binding pockets that possess physicochemical features typically found in pockets considered druggable. Small-molecule binding to these pockets may stabilize this autoinhibited structure of KRAS if it exists in cells to provide a new strategy to inhibit RAS signaling.

SUBMITTER: Brenner RJ 

PROVIDER: S-EPMC10904212 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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

Brenner Robert J RJ   Landgraf Alexander D AD   Bum-Erdene Khuchtumur K   Gonzalez-Gutierrez Giovanni G   Meroueh Samy O SO  

Biochemistry 20231108 22


KRAS GTPases harbor oncogenic mutations in more than 25% of human tumors. KRAS is considered to be largely undruggable due to the lack of a suitable small-molecule binding site. Here, we report a unique crystal structure of His-tagged KRAS<sup>G12D</sup> that reveals a remarkable conformational change. The Switch I loop of one His-KRAS<sup>G12D</sup> structure extends into the Switch I/II pocket of another His-KRAS<sup>G12D</sup> in an adjacent unit cell to create an elaborate interface that is  ...[more]

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