Nature Structural Biology10, 820 - 825 (2003)
Published online: 7 September 2003; | doi:10.1038/nsb979
All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR
Catherine Stehlin-Gaon1, 4, Dominica Willmann2, 4, Denis Zeyer1, Sarah Sanglier3, Alain Van Dorsselaer3, Jean-Paul Renaud1, Dino Moras1
& Roland Schüle2
1
Département de Biologie et Génomique Structurales, Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, 67404 Illkirch, France.
2
Universitäts-Frauenklinik, Zentrum für Klinische Forschung, Klinikum der Universität Freiburg, Breisacherstrasse 66, 79106 Freiburg, Germany.
3
Laboratoire de Spectrométrie de Masse Bio-Organique, Ecole de Chimie, Polymères et Matériaux, 25 rue Becquerel, 67087 Strasbourg, France.
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 and (ROR and ) have been identified, yet structural data and structure-function analyses indicate that ROR 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 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 but not ROR transcriptional activity suggesting that high-affinity, subtype-specific ligands could be designed for the identification of ROR target genes. Our results identify ROR as a retinoid-regulated nuclear receptor, providing a novel pathway for retinoid action.
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transcriptional activity suggesting that high-affinity, subtype-specific ligands could be designed for the identification of ROR
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