{"doi":"10.1101/2024.01.10.574970","title":"Active site remodeling in tumor-relevant IDH1 mutants drives distinct kinetic features and potential resistance mechanisms","abstract":"Mutations in human isocitrate dehydrogenase 1 (IDH1) drive tumor formation in a variety of cancers by replacing its conventional activity with a neomorphic activity that generates an oncometabolite. Little is understood of the mechanistic differences among tumor-driving IDH1 mutants. We previously reported that the R132Q mutant uniquely preserves conventional activity while catalyzing robust oncometabolite production, allowing an opportunity to compare these reaction mechanisms within a single active site. Here, we employed static and dynamic structural methods and found that, compared to R132H, the R132Q active site adopted a conformation primed for catalysis with optimized substrate binding and hydride transfer to drive improved conventional and neomorphic activity over R132H. This active site remodeling revealed a possible mechanism of resistance to selective mutant IDH1 therapeutic inhibitors. This work enhances our understanding of fundamental IDH1 mechanisms while pinpointing regions for improving inhibitor selectivity.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":489625,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9553,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1296847,"name":"Nicole A. Sierra","orcid":null,"position":1,"is_corresponding":false},{"id":1121159,"name":"Diego Avellaneda Matteo","orcid":null,"position":2,"is_corresponding":false},{"id":1121157,"name":"Elene Albekioni","orcid":null,"position":3,"is_corresponding":false},{"id":1296848,"name":"Rachel Khoury","orcid":null,"position":4,"is_corresponding":false},{"id":1296849,"name":"Timothy Mai","orcid":null,"position":5,"is_corresponding":false},{"id":1296850,"name":"Brittany M. Conley","orcid":null,"position":6,"is_corresponding":false},{"id":1120758,"name":"Nalani J. Coleman","orcid":"0000-0002-1357-7736","position":7,"is_corresponding":false},{"id":1121156,"name":"Kaitlyn A. Sabo","orcid":null,"position":8,"is_corresponding":false},{"id":318431,"name":"Elizabeth A. Komives","orcid":"0000-0001-5264-3866","position":9,"is_corresponding":false},{"id":376203,"name":"Andrey A. Bobkov","orcid":"0000-0002-9028-3635","position":10,"is_corresponding":false},{"id":1296493,"name":"Andrew L. Cooksy","orcid":"0000-0002-2794-4269","position":11,"is_corresponding":false},{"id":238647,"name":"Steve Silletti","orcid":null,"position":12,"is_corresponding":false},{"id":580586,"name":"Jamie M. Schiffer","orcid":"0000-0002-0208-6958","position":13,"is_corresponding":false},{"id":763617,"name":"Tom Huxford","orcid":"0000-0002-1939-7373","position":14,"is_corresponding":false},{"id":580587,"name":"Christal D. Sohl","orcid":"0000-0002-8048-0205","position":15,"is_corresponding":false},{"id":1116746,"name":"Matthew Mealka","orcid":null,"position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-19T02:08:28.548530Z","pmid":"38260668","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":[]}