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

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 (RORbeta and gamma) have been identified, yet structural data and structure-function analyses indicate that RORbeta 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 RORbeta 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 RORbeta but not RORalpha transcriptional activity suggesting that high-affinity, subtype-specific ligands could be designed for the identification of RORbeta target genes. Our results identify RORbeta as a retinoid-regulated nuclear receptor, providing a novel pathway for retinoid action.