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

ALBA JIMENEZ-PANIZO; ANDREA ALEGRE-MARTÍ; THEOPHILUS TETTEY; GREGORY FETTWEIS; MONTSERRAT ABELLA; ROSA ANTÓN; THOMAS A JOHNSON; KIM, SOHYOUNG; R. LOUIS SCHILTZ; ISRAEL NUÑEZ-BARRIOS; JOAN FONT-DÍAZ; CARME CAELLES; ANNABEL F. VALLEDOR; PALOMA PÉREZ; ANA M. ROJAS; JUAN FERNÁNDEZ-RECIO; DIEGO M PRESMAN; GORDON L. HAGER; PABLO FUENTES-PRIOR; EVA ESTÉBANEZ-PERPIÑÁ

Floriana

Congreso; A 20/20 vision of the future of nuclear receptors; 2022

EMBO

The glucocorticoid receptor (GR) is a ubiquitously expressed transcription factor thatcontrols metabolic and homeostatic processes essential for life. Although numerouscrystal structures of the GR ligand-binding domain (GR-LBD) have been reported, thefunctional oligomeric state of the full-length receptor, which is essential for itstranscriptional activity, remains disputed. Here we present five new crystal structures ofagonist-bound GR-LBD, along with a thorough analysis of previous structural work.Biologically relevant homodimers were identified by studying a battery of GR pointmutants including crosslinking assays in solution and quantitative fluorescencemicroscopy in living cells. Our results highlight the relevance of non-canonicaldimerization modes for GR, especially of contacts made by loop L1-3 residues such asTyr545. Our work unveils likely pathophysiologically relevant quaternary assemblies ofthe nuclear receptor with important implications for glucocorticoid action and drugdesign.