Quaternary glucocorticoid receptor structure highlights allosteric interdomain communication - Archive ouverte HAL Access content directly
Journal Articles Nature Structural and Molecular Biology Year : 2023

Quaternary glucocorticoid receptor structure highlights allosteric interdomain communication

Abstract

The glucocorticoid receptor (GR) is a ligand activated transcription factor that binds DNA and assembles context dependent coregulator complexes to regulate gene transcription. GR agonists are widely prescribed to patients with inflammatory and autoimmune diseases. Here, we determine the first high resolution, multi-domain structures of GR in complex with ligand, DNA and a coregulator peptide. The structures reveal how the receptor forms an asymmetric dimer on the DNA and provide a detailed view of the domain interactions within and across the two monomers. Hydrogen deuterium exchange and DNA binding experiments 2 demonstrate that ligand dependent structural changes are communicated across the different domains in the full-length receptor. Based on the structural analysis, we design mutant receptor constructs and functional assays to validate the signaling pathways identified in the structures. This study demonstrates how GR forms a distinct architecture on DNA and how signal transmission can be modulated by the ligand pharmacophore. The results provide a platform where we can build a new level of understanding for how receptor modifications can drive disease progression and offer key insight for future drug design.
Fichier principal
Vignette du fichier
Postel_et_al_revised.pdf (2.77 Mo) Télécharger le fichier
Origin : Files produced by the author(s)
Licence : CC BY - Attribution

Dates and versions

hal-04281562 , version 1 (13-11-2023)

Licence

Attribution

Identifiers

Cite

Sandra Postel, Lisa Wissler, Carina Johansson, Anders Gunnarsson, Euan Gordon, et al.. Quaternary glucocorticoid receptor structure highlights allosteric interdomain communication. Nature Structural and Molecular Biology, 2023, 30 (3), pp.286-295. ⟨10.1038/s41594-022-00914-4⟩. ⟨hal-04281562⟩
21 View
16 Download

Altmetric

Share

Gmail Facebook X LinkedIn More