Stehlin-Gaon Catherine, Willmann Dominica, Zeyer Denis, Sanglier Sarah, Van Dorsselaer Alain, Renaud Jean-Paul, Moras Dino, Schüle Roland
Département de Biologie et Génomique Structurales, Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, 67404 Illkirch, France.
Nat Struct Biol. 2003 Oct;10(10):820-5. doi: 10.1038/nsb979. Epub 2003 Sep 7.
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.
维甲酸通过与核视黄酸受体（RARs）和视黄醇X受体（RXRs）结合来调节基因表达。相比之下，尚未鉴定出视黄酸受体相关孤儿受体β和γ（RORβ和γ）的配体，但结构数据和结构功能分析表明RORβ是一种配体调节的核受体。使用非变性质谱和闪烁邻近分析，我们发现全反式维甲酸（ATRA）和几种维甲酸与RORβ配体结合域（LBD）结合。与ATRA和合成类似物ALRT 1550形成的复合物的晶体结构揭示了这些配体的结合模式。ATRA和相关维甲酸抑制RORβ而非RORα的转录活性，这表明可以设计高亲和力、亚型特异性配体来鉴定RORβ靶基因。我们的结果确定RORβ为一种维甲酸调节的核受体，为维甲酸作用提供了一条新途径。
