{"doi":"10.1021/acs.biochem.3c00378","title":"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 KRAS G12D that reveals a remarkable conformational change. The Switch I loop of one His-KRAS G12D structure extends into the Switch I/II pocket of another His-KRAS G12D 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.","journal":"Biochemistry","year":2023,"id":373764,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9461,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1121468,"name":"Alexander D. Landgraf","orcid":"0000-0001-6647-037X","position":1,"is_corresponding":false},{"id":456382,"name":"Khuchtumur Bum‐Erdene","orcid":"0000-0003-3222-7384","position":2,"is_corresponding":false},{"id":456383,"name":"Giovanni González-Gutiérrez","orcid":"0000-0002-1044-943X","position":3,"is_corresponding":false},{"id":456386,"name":"Samy O. Meroueh","orcid":"0000-0002-3948-7499","position":4,"is_corresponding":false},{"id":1135447,"name":"Robert J. Brenner","orcid":null,"position":0,"is_corresponding":true}],"reference_count":29,"raw_metadata":null,"created_at":"2026-07-19T01:16:07.080027Z","pmid":"37938120","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}