All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta

Catherine Stehlin-Gaon (1) , Dominica Willmann (2) , Denis Zeyer (1) , Sarah Sanglier (3) , Alain van Dorsselaer (4) , Jean-Paul Renaud (1) , Dino Moras (1) , Roland Schüle (2)

1 IGBMC - Institut de génétique et biologie moléculaire et cellulaire
2 Uniklinik - Universitäts Klinikum Freiburg = University Medical Center Freiburg
3 Ecole européenne de chimie, polymères et matériaux [Strasbourg]
4 LSMBO - Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg]

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.

Domaines: Biochimie, Biologie Moléculaire

Catherine Stehlin-Gaon, Dominica Willmann, Denis Zeyer, Sarah Sanglier, Alain van Dorsselaer, et al.. All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta. Nature Structural Biology, 2003, 10 (10), pp.820-825. ⟨10.1038/nsb979⟩. ⟨hal-04151448⟩