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