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The multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities

ABSTRACT: The glucocorticoid receptor (GR) is a ubiquitously expressed transcription factor that controls metabolic and homeostatic processes essential for life. Although numerous crystal structures of the GR ligand-binding domain (GR-LBD) have been reported, the functional oligomeric state of the full-length receptor, which is essential for its transcriptional activity, remains disputed. Here we present five new crystal structures of agonist-bound GR-LBD, along with a thorough analysis of previous structural work. Biologically relevant homodimers were identified by studying a battery of GR point mutants including crosslinking assays in solution and quantitative fluorescence microscopy in live cells. Our results highlight the relevance of non-canonical dimerization modes for GR, especially of contacts made by loop L1-3 residues such as Tyr545. Our work unveils likely pathophysiologically relevant quaternary assemblies of the nuclear receptor with important implications for glucocorticoid action and drug design.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Marina Gay

LAB HEAD: Eva Estébanez-Perpiñá

PROVIDER: PXD028039 | Pride | 2023-03-11

REPOSITORIES: Pride

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The multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities.

Jiménez-Panizo Alba A Alegre-Martí Andrea A Tettey Theophilus T TT Fettweis Gregory G Abella Montserrat M Antón Rosa R Johnson Thomas A TA Kim Sohyoung S Schiltz R Louis RL Núñez-Barrios Israel I Font-Díaz Joan J Caelles Carme C Valledor Annabel F AF Pérez Paloma P Rojas Ana M AM Fernández-Recio Juan J Presman Diego M DM Hager Gordon L GL Fuentes-Prior Pablo P Estébanez-Perpiñá Eva E

Nucleic acids research 20221201 22

The glucocorticoid receptor (GR) is a ubiquitously expressed transcription factor that controls metabolic and homeostatic processes essential for life. Although numerous crystal structures of the GR ligand-binding domain (GR-LBD) have been reported, the functional oligomeric state of the full-length receptor, which is essential for its transcriptional activity, remains disputed. Here we present five new crystal structures of agonist-bound GR-LBD, along with a thorough analysis of previous struct ...[more]

PMID: 36464162

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			Action	DRS
	3324_AJ_Dimer-Chymo.raw	Raw
	3324_AJ_Dimer-Tryp.raw	Raw
	3324_AJ_Tetramer-Chymo.raw	Raw
	3324_AJ_Tetramer-Tryp.raw	Raw
	3324_AJ_chymo_mod.zhrs	Other