Database: PubMedEntry: 11689423
Original site: 11689423
Stehlin C, Wurtz JM, Steinmetz A, Greiner E, Schule R, Moras D,
X-ray structure of the orphan nuclear receptor RORbeta ligand-binding domain in
the active conformation.
EMBO J. 2001 Nov 1;20(21):5822-31.
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.
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