8FFV

Cryo-EM structure of the GR-Hsp90-FKBP52 complex

Summary for 8FFV

• Entry DOI: 10.2210/pdb8ffv/pdb
• EMDB information: 29068 29069
• Descriptor: Heat shock protein HSP 90-alpha, Glucocorticoid receptor, Peptidyl-prolyl cis-trans isomerase FKBP4, N-terminally processed, ... (6 entities in total)
• Functional Keywords: chaperone, steroid hormone receptor, ligand binding, atp binding, protein folding
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 263831.99

Authors

Noddings, C.M.,Agard, D.A. (deposition date: 2022-12-10, release date: 2023-11-01, Last modification date: 2023-12-20)

Primary citation

Noddings, C.M.,Johnson, J.L.,Agard, D.A.
Cryo-EM reveals how Hsp90 and FKBP immunophilins co-regulate the glucocorticoid receptor.
Nat.Struct.Mol.Biol., 30:1867-1877, 2023

PubMed Abstract: Hsp90 is an essential molecular chaperone responsible for the folding and activation of hundreds of 'client' proteins, including the glucocorticoid receptor (GR). Previously, we revealed that Hsp70 and Hsp90 remodel the conformation of GR to regulate ligand binding, aided by co-chaperones. In vivo, the co-chaperones FKBP51 and FKBP52 antagonistically regulate GR activity, but a molecular understanding is lacking. Here we present a 3.01 Å cryogenic electron microscopy structure of the human GR:Hsp90:FKBP52 complex, revealing how FKBP52 integrates into the GR chaperone cycle and directly binds to the active client, potentiating GR activity in vitro and in vivo. We also present a 3.23 Å cryogenic electron microscopy structure of the human GR:Hsp90:FKBP51 complex, revealing how FKBP51 competes with FKBP52 for GR:Hsp90 binding and demonstrating how FKBP51 can act as a potent antagonist to FKBP52. Altogether, we demonstrate how FKBP51 and FKBP52 integrate into the GR chaperone cycle to advance GR to the next stage of maturation.

PubMed: 37945740
DOI: 10.1038/s41594-023-01128-y

Experimental method

ELECTRON MICROSCOPY (3.01 Å)