1K4W

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

Summary for 1K4W

• Entry DOI: 10.2210/pdb1k4w/pdb
• Related: 2LBD
• Descriptor: Nuclear receptor ROR-beta, steroid receptor coactivator-1, STEARIC ACID, ... (4 entities in total)
• Functional Keywords: ligand-binding domain, alpha-helical sandwich, transcriptionally active conformation, hormone-growth factor complex, hormone/growth factor
• Biological source: Rattus norvegicus (Norway rat); More
• Cellular location: Nucleus (Probable): P45446
• Total number of polymer chains: 2
• Total formula weight: 30962.01

Authors

Stehlin, C.,Wurtz, J.M.,Steinmetz, A.,Greiner, E.,Schuele, R.,Moras, D.,Renaud, J.P. (deposition date: 2001-10-09, release date: 2002-04-09, Last modification date: 2023-08-16)

Primary citation

Stehlin, C.,Wurtz, J.M.,Steinmetz, A.,Greiner, E.,Schule, R.,Moras, D.,Renaud, J.P.
X-ray structure of the orphan nuclear receptor RORbeta ligand-binding domain in the active conformation.
EMBO J., 20:5822-5831, 2001

PubMed Abstract: 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.

PubMed: 11689423
DOI: 10.1093/emboj/20.21.5822

Experimental method

X-RAY DIFFRACTION (1.9 Å)