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| The EMBO Journal
(2001) 20, 5822–5831, doi:10.1093/emboj/20.21.5822 |
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X-ray structure of the orphan nuclear receptor ROR ligand-binding domain in the active conformation |
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| Catherine Stehlin1, Jean-Marie Wurtz1, Anke Steinmetz1, Erich Greiner2, 3, Roland Schüle2, Dino Moras1 and Jean-Paul Renaud1 |
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1 Laboratoire de Biologie et Génomique Structurales (CNRS Unité Propre de Recherche 9004), Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS/INSERM/Université Louis Pasteur), 1 rue Laurent Fries, BP 163, 67404 Illkirch, France 2 Universitäts-Frauenklinik, Zentrum fur Klinische Forschung, Klinikum der Universität Freiburg, Breisacherstrasse 66, D-79106 Freiburg, Germany 3 Present address: German Cancer Research Center, Division of Molecular Biology of the Cell, D-69120 Heidelberg, Germany To whom correspondence should be addressed Dino Moras, moras@igbmc.u-strasbg.fr Received 25 July 2001; Revised 17 September 2001; Accepted 17 September 2001. |
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| Abstract |
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| The retinoic acid-related orphan receptor (ROR) exhibits a highly restricted neuronal-specific expression pattern in brain, retina and pineal gland. So far, neither a natural ROR target gene nor a functional ligand have been identified, and the physiological role of the receptor is not well understood. We present the crystal structure of the ligand-binding domain (LBD) of ROR containing a bound stearate ligand and complexed with a coactivator peptide. In the crystal, the monomeric LBD adopts the canonical agonist-bound form. The fatty acid ligand–coactivator peptide combined action stabilizes the transcriptionally active conformation. The large ligand-binding pocket is strictly hydrophobic on the AF-2 side and more polar on the -sheet side where the carboxylate group of the ligand binds. Site-directed mutagenesis experiments validate the significance of the present structure. Homology modeling of the other isotypes will help to design isotype-selective agonists and antagonists that can be used to characterize the physiological functions of RORs. In addition, our crystallization strategy can be extended to other orphan nuclear receptors, providing a powerful tool to delineate their functions. |
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| Keywords: crystal structure, nuclear receptor, orphan, ROR, RZR |
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