Structure of Hsp90-p23-GR reveals the Hsp90 client-remodelling mechanism

Nature. 2022 Jan;601(7893):465-469. doi: 10.1038/s41586-021-04236-1. Epub 2021 Dec 22.


Hsp90 is a conserved and essential molecular chaperone responsible for the folding and activation of hundreds of 'client' proteins1-3. The glucocorticoid receptor (GR) is a model client that constantly depends on Hsp90 for activity4-9. GR ligand binding was previously shown to nr inhibited by Hsp70 and restored by Hsp90, aided by the co-chaperone p2310. 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 structure11. Thus, aided by direct co-chaperone-client interactions, Hsp90 can directly dictate client-specific folding outcomes. Together with the GR-loading complex structure12, we present the molecular mechanism of chaperone-mediated GR remodelling, establishing the first, to our knowledge, complete chaperone cycle for any Hsp90 client.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cryoelectron Microscopy*
  • HSP70 Heat-Shock Proteins / chemistry
  • HSP70 Heat-Shock Proteins / metabolism
  • HSP70 Heat-Shock Proteins / ultrastructure
  • HSP90 Heat-Shock Proteins* / chemistry
  • HSP90 Heat-Shock Proteins* / metabolism
  • HSP90 Heat-Shock Proteins* / ultrastructure
  • Humans
  • Ligands
  • Molecular Chaperones / chemistry
  • Molecular Chaperones / metabolism
  • Molecular Chaperones / ultrastructure
  • Prostaglandin-E Synthases* / chemistry
  • Prostaglandin-E Synthases* / metabolism
  • Prostaglandin-E Synthases* / ultrastructure
  • Protein Binding
  • Receptors, Glucocorticoid* / chemistry
  • Receptors, Glucocorticoid* / metabolism
  • Receptors, Glucocorticoid* / ultrastructure


  • HSP70 Heat-Shock Proteins
  • HSP90 Heat-Shock Proteins
  • Ligands
  • Molecular Chaperones
  • Receptors, Glucocorticoid
  • PTGES3 protein, human
  • Prostaglandin-E Synthases