{"doi":"10.1101/2021.08.10.455711","title":"Cryo-EM reveals disrupted human p97 allosteric activation by disease mutations and inhibitor binding","abstract":"ABSTRACT The human AAA ATPase p97, a potential cancer target, plays a vital role in clearing misfolded proteins. p97 dysfunction is also known to play a crucial role in several neurodegenerative disorders. Here, we present cryo-EM structural analyses of four disease mutants p97 R155H , p97 R191Q , p97 A232E , p97 D592N , as well as p97 E470D , implicated in resistance to the drug CB-5083. These structures demonstrate that the mutations affect nucleotide-driven p97 allosteric activation by predominantly interfering with either the coupling between the D1 and N-terminal domains (p97 R155H and p97 R191Q ), the inter-protomer interactions (p97 A232E ), or the coupling between D1 and D2 nucleotide domains (p97 D592N , p97 E470D ). We also show that binding of the competitive inhibitor CB-5083 to the D2 domain prevents conformational changes similar to that seen for mutations that affect coupling between D1 and D2 domains. Our studies enable tracing of the path of allosteric activation across p97 and establish a common mechanistic link between active site inhibition and defects in allosteric activation by disease-causing mutations.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":226134,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.946,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":267230,"name":"Xing Zhu","orcid":"0000-0003-4839-4857","position":1,"is_corresponding":false},{"id":267225,"name":"Alison Berezuk","orcid":"0000-0001-8512-0180","position":2,"is_corresponding":false},{"id":320860,"name":"Katharine S. Tuttle","orcid":"0000-0002-9788-1830","position":3,"is_corresponding":false},{"id":267226,"name":"Sagar Chittori","orcid":"0000-0003-1417-6552","position":4,"is_corresponding":false},{"id":267232,"name":"Sriram Subramaniam","orcid":"0000-0003-4231-4115","position":5,"is_corresponding":false},{"id":695014,"name":"Brian J. Caffrey","orcid":"0000-0001-5040-4247","position":0,"is_corresponding":true}],"reference_count":34,"raw_metadata":null,"created_at":"2026-07-18T23:54:34.185847Z","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":[]}