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Here, we integrated X-ray crystallography with native mass spectrometry and ultraviolet photodissociation (nMS-UVPD) to reveal a cryptic conformation in the oncogenic Y42C mutant of RhoA. While crystallography alone resolved two ambiguous structures, nMS-UVPD determined the dominant conformation by directly mapping the mutant’s conformational dynamics, identifying an enhanced Mg 2+ -locked conformation. We explored the mechanism of mutation impairing GTP hydrolysis. This state unmasks a previously hidden, druggable pocket adjacent to Cys42, guiding our identification of a covalent inhibitor. Our integrated approach establishes a roadmap for targeting pathogenic protein mutants previously considered “undruggable” due to their highly dynamic nature.","is_dataset_classified":null,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"41837560","pmcid":null,"openalex_id":"https://openalex.org/W7136329004","authors":[],"funders":[{"funder_name":"National Key Research and Development Program of China","grant_id":"2021ZD0203900","title":null},{"funder_name":"National Key Research and Development Program of China","grant_id":"2022YFC3400500","title":null},{"funder_name":"National Key Research and Development Program of China","grant_id":"2025YFA1309300","title":null},{"funder_name":"Science and Technology Commission of Shanghai Municipality","grant_id":"YDZX20233100004032","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"22337004","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"22377089","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"22525406","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"22574159","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"81821005","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"82341017","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"92253303","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"U23A20108","title":null},{"funder_name":"Chinese Academy of Sciences","grant_id":"XDB0970100","title":null},{"funder_name":"Major Program of Guangzhou National Laboratory","grant_id":"GZNL2023A02012","title":null},{"funder_name":"Shandong Laboratory Program","grant_id":"SYS202205","title":null},{"funder_name":"Zhongshan Institute for Drug Discovery","grant_id":"ZIDD202302","title":null}],"total_grants":16,"fwci":4.1776,"citation_percentile":0.92064282,"influential_citations":0,"citation_trend":[{"year":2026,"count":1}],"oa_status":"closed","license":"https://doi.org/10.15223/policy-029","oa_locations":[{"url":"https://pubs.acs.org/doi/pdf/10.1021/jacs.5c20067","host_type":"publisher"},{"url":"https://doi.org/10.1021/jacs.5c20067","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/41837560","host_type":"repository"}],"fields_of_study":["Protein Kinase Regulation and GTPase Signaling","Enzyme Structure and Function","Advanced Proteomics Techniques and Applications","rhoA GTP-Binding Protein","Mutation","Mass Spectrometry","Ultraviolet Rays","Protein Conformation","Crystallography, X-Ray","Models, Molecular","X-Ray Diffraction","Humans"],"mesh_terms":["Humans","Models, Molecular","Mutation","Protein Conformation","Mass Spectrometry","Ultraviolet Rays","X-Ray Diffraction","Crystallography, X-Ray","rhoA GTP-Binding Protein"],"keywords":["Druggability","Mutant","Photodissociation","Mass spectrometry","Mutation","Covalent bond","Protein structure","GTPase"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-03T06:32:38.090571Z","pmid":null,"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":[]}