Hsp90 is a conserved and essential molecular chaperone responsible for the folding and activation of hundreds of ‘client’ proteins,. The glucocorticoid receptor (GR) is a model client that constantly depends on Hsp90 for activity. Previously, we revealed GR ligand binding is inhibited by Hsp70 and restored by Hsp90, aided by the cochaperone p23. 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. 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. ### Competing Interest Statement The authors have declared no competing interest. : #ref-1 : #ref-2 : #ref-3 : #ref-4 : #ref-5
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