{"doi":"10.1101/2020.09.12.294975","title":"GR chaperone cycle mechanism revealed by cryo-EM: reactivation of GR by the GR:Hsp90:p23 client-maturation complex","abstract":"Abstract Hsp90 is a conserved and essential molecular chaperone responsible for the folding and activation of hundreds of ‘client’ proteins 1,2 . The glucocorticoid receptor (GR) is a model client that constantly depends on Hsp90 for activity 3 . Previously, we revealed GR ligand binding is inhibited by Hsp70 and restored by Hsp90, aided by the cochaperone p23 4 . However, a molecular understanding of the chaperone-induced transformations that occur between the inactive Hsp70:Hsp90 ‘client-loading complex’ and an activated Hsp90:p23 ‘client-maturation complex’ is lacking for GR, or for any client. Here, we present a 2.56Å cryo-EM structure of the GR-maturation complex (GR:Hsp90:p23), revealing that the GR ligand binding domain is, surprisingly, restored to a folded, ligand-bound conformation, while simultaneously threaded through the Hsp90 lumen. Also, unexpectedly, p23 directly stabilizes native GR using a previously uncharacterized C-terminal helix, resulting in enhanced ligand-binding. This is the highest resolution Hsp90 structure to date and the first atomic resolution structure of a client bound to Hsp90 in a native conformation, sharply contrasting with the unfolded kinase:Hsp90 structure 5 . Thus, aided by direct cochaperone:client interactions, Hsp90 dictates client-specific folding outcomes. Together with the GR-loading complex structure (Wang et al. 2020), we present the molecular mechanism of chaperone-mediated GR remodeling, establishing the first complete chaperone cycle for any client.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":119644,"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":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9543,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":555486,"name":"Ray Yu‐Ruei Wang","orcid":"0000-0001-5025-9596","position":1,"is_corresponding":false},{"id":98189,"name":"David A. Agard","orcid":"0000-0003-3512-695X","position":2,"is_corresponding":false},{"id":489208,"name":"Feng Wang","orcid":"0000-0003-0890-9035","position":0,"is_corresponding":true}],"reference_count":25,"raw_metadata":null,"created_at":"2026-07-18T23:14:13.002105Z","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":[]}