8FMJ

Crystal structure of human KRAS in space group R32

Summary for 8FMJ

• Entry DOI: 10.2210/pdb8fmj/pdb
• Descriptor: GTPase KRas, MAGNESIUM ION, GLYCEROL, ... (7 entities in total)
• Functional Keywords: cancer, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 21061.67

Authors

Brenner, R.,Landgraf, A.,Gonzalez-Gutierrez, G.,Bum-Erdene, K.,Meroueh, S.O. (deposition date: 2022-12-23, release date: 2023-11-22, Last modification date: 2023-12-06)

Primary citation

Brenner, R.J.,Landgraf, A.D.,Bum-Erdene, K.,Gonzalez-Gutierrez, G.,Meroueh, S.O.
Crystal Packing Reveals a Potential Autoinhibited KRAS Dimer Interface and a Strategy for Small-Molecule Inhibition of RAS Signaling.
Biochemistry, 62:3206-3213, 2023

PubMed 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 KRAS that reveals a remarkable conformational change. The Switch I loop of one His-KRAS structure extends into the Switch I/II pocket of another His-KRAS 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.

PubMed: 37938120
DOI: 10.1021/acs.biochem.3c00378

Experimental method

X-RAY DIFFRACTION (1.33 Å)