7KRJ

The GR-Maturation Complex: Glucocorticoid Receptor in complex with Hsp90 and co-chaperone p23

Summary for 7KRJ

• Entry DOI: 10.2210/pdb7krj/pdb
• EMDB information: 23004
• Descriptor: Heat shock protein HSP 90-alpha, Prostaglandin E synthase 3, Glucocorticoid receptor, ... (6 entities in total)
• Functional Keywords: ligand binding, atp binding, protein folding, cryo-em, chaperone
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 219664.15

Authors

Noddings, C.M.,Wang, Y.-R.,Agard, D.A. (deposition date: 2020-11-20, release date: 2022-01-12, Last modification date: 2024-05-29)

Primary citation

Noddings, C.M.,Wang, R.Y.,Johnson, J.L.,Agard, D.A.
Structure of Hsp90-p23-GR reveals the Hsp90 client-remodelling mechanism.
Nature, 601:465-469, 2021

PubMed Abstract: 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. GR ligand binding was previously shown to nr inhibited by Hsp70 and restored by Hsp90, aided by the co-chaperone p23. However, a molecular understanding of the chaperone-mediated remodelling that occurs between the inactive Hsp70-Hsp90 'client-loading complex' and an activated Hsp90-p23 'client-maturation complex' is lacking for any client, including GR. Here we present a cryo-electron microscopy (cryo-EM) structure of the human GR-maturation complex (GR-Hsp90-p23), revealing that the GR ligand-binding domain is restored to a folded, ligand-bound conformation, while being simultaneously threaded through the Hsp90 lumen. In addition, p23 directly stabilizes native GR using a C-terminal helix, resulting in enhanced ligand binding. This structure of a client bound to Hsp90 in a native conformation contrasts sharply with the unfolded kinase-Hsp90 structure. Thus, aided by direct co-chaperone-client interactions, Hsp90 can directly dictate client-specific folding outcomes. Together with the GR-loading complex structure, we present the molecular mechanism of chaperone-mediated GR remodelling, establishing the first, to our knowledge, complete chaperone cycle for any Hsp90 client.

PubMed: 34937936
DOI: 10.1038/s41586-021-04236-1

Experimental method

ELECTRON MICROSCOPY (2.56 Å)