title: All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta.
abstract: Retinoids regulate gene expression through binding to the nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs). In contrast, no ligands for the retinoic acid receptor-related orphan receptors beta and gamma (ROR beta and gamma) have been identified, yet structural data and structure-function analyses indicate that ROR beta is a ligand-regulated nuclear receptor. Using nondenaturing mass spectrometry and scintillation proximity assays we found that all-trans retinoic acid (ATRA) and several retinoids bind to the ROR beta ligand-binding domain (LBD). The crystal structures of the complex with ATRA and with the synthetic analog ALRT 1550 reveal the binding modes of these ligands. ATRA and related retinoids inhibit ROR beta but not ROR alpha transcriptional activity suggesting that high-affinity, subtype-specific ligands could be designed for the identification of ROR beta target genes. Our results identify ROR beta as a retinoid-regulated nuclear receptor, providing a novel pathway for retinoid action.
authors.affiliation: Département de Biologie et Génomique Structurales, Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, 67404 Illkirch, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Stehlin-Gaon
authors.forename: Dominica
authors.initials: D
authors.lastname: Willmann
authors.forename: Denis
authors.initials: D
authors.lastname: Zeyer
authors.forename: Sarah
authors.initials: S
authors.lastname: Sanglier
authors.forename: Alain
authors.initials: A
authors.lastname: Van Dorsselaer
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Renaud
authors.forename: Dino
authors.initials: D
authors.lastname: Moras
authors.forename: Roland
authors.initials: R
authors.lastname: Schüle
mesh_terms: D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D057095:Nuclear Receptor Subfamily 1, Group F, Member 2; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D008024:Ligands; D057095:Nuclear Receptor Subfamily 1, Group F, Member 2; D018160:Receptors, Cytoplasmic and Nuclear; D014212:Tretinoin