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  • The EMBO Journal (2001) 20, 5822 - 5831
  • doi:10.1093/emboj/20.21.5822

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

Catherine Stehlin1, Jean-Marie Wurtz1, Anke Steinmetz1, Erich Greiner2,3, Roland Schüle2, Dino Moras1 and Jean-Paul Renaud1

  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

Correspondence to:

Dino Moras, E-mail: moras@igbmc.u-strasbg.fr

Received 25 July 2001; Accepted 17 September 2001; Revised 17 September 2001

The retinoic acid-related orphan receptor beta (RORbeta) exhibits a highly restricted neuronal-specific expression pattern in brain, retina and pineal gland. So far, neither a natural RORbeta 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 RORbeta 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 beta-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.

  • Keywords:

    • crystal structure,
    • nuclear receptor,
    • orphan,
    • ROR,
    • RZR