Crystal Packing Reveals a Potential Autoinhibited KRAS Dimer Interface and a Strategy for Small-Molecule Inhibition of RAS Signaling
dc.contributor.author | Brenner, Robert J. | |
dc.contributor.author | Landgraf, Alexander D. | |
dc.contributor.author | Bum-Erdene, Khuchtumur | |
dc.contributor.author | Gonzalez-Gutierrez, Giovanni | |
dc.contributor.author | Meroueh, Samy O. | |
dc.contributor.department | Biochemistry and Molecular Biology, School of Medicine | |
dc.date.accessioned | 2024-06-11T13:13:36Z | |
dc.date.available | 2024-06-11T13:13:36Z | |
dc.date.issued | 2023 | |
dc.description.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. | |
dc.eprint.version | Author's manuscript | |
dc.identifier.citation | Brenner RJ, Landgraf AD, Bum-Erdene K, Gonzalez-Gutierrez G, Meroueh SO. Crystal Packing Reveals a Potential Autoinhibited KRAS Dimer Interface and a Strategy for Small-Molecule Inhibition of RAS Signaling. Biochemistry. 2023;62(22):3206-3213. doi:10.1021/acs.biochem.3c00378 | |
dc.identifier.uri | https://hdl.handle.net/1805/41405 | |
dc.language.iso | en_US | |
dc.publisher | American Chemical Society | |
dc.relation.isversionof | 10.1021/acs.biochem.3c00378 | |
dc.relation.journal | Biochemistry | |
dc.rights | Publisher Policy | |
dc.source | PMC | |
dc.subject | Amino acids | |
dc.subject | Molecular dynamics simulation | |
dc.subject | Mutation | |
dc.subject | Protein binding | |
dc.subject | Signal transduction | |
dc.title | Crystal Packing Reveals a Potential Autoinhibited KRAS Dimer Interface and a Strategy for Small-Molecule Inhibition of RAS Signaling | |
dc.type | Article |