All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta.
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.
Stehlin-Gaon
Catherine
C
Département de Biologie et Génomique Structurales, Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, 67404 Illkirch, France.
Willmann
Dominica
D
Zeyer
Denis
D
Sanglier
Sarah
S
Van Dorsselaer
Alain
A
Renaud
Jean-Paul
JP
Moras
Dino
D
Schüle
Roland
R
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*
D008024:Ligands; D057095:Nuclear Receptor Subfamily 1, Group F, Member 2; D018160:Receptors, Cytoplasmic and Nuclear; D014212:Tretinoin