X-ray structure of the orphan nuclear receptor ROR beta ligand-binding domain in the active conformation

The retinoic acid-related orphan receptor beta (ROR beta) exhibits a highly restricted neuronal-specific expression pattern in brain, retina and pinea l gland. So far, neither a natural ROR beta target gene nor a functional li gand have been identified, and the physiological role of the receptor is no t well understood. We present the crystal structure of the ligand-binding d omain (LBD) of ROR beta containing a bound stearate ligand and complexed wi th a coactivator peptide. In the crystal, the monomeric LBD adopts the cano nical agonist-bound form. The fatty acid ligand-coactivator peptide combine d action stabilizes the transcriptionally active conformation. The large li gand-binding pocket is strictly hydrophobic on the AF-2 side and more polar on the beta -sheet side where the carboxylate group of the ligand binds. S ite-directed mutagenesis experiments validate the significance of the prese nt structure. Homology modeling of the other isotypes will help to design i sotype-selective agonists and antagonists that can be used to characterize the physiological functions of RORs. In addition, our crystallization strat egy can be extended to other orphan nuclear receptors, providing a powerful tool to delineate their functions.