X-Ray Structure of the hRORα LBD at 1.63 Å Structural and Functional Data that Cholesterol or a Cholesterol Derivative Is the Natural Ligand of RORα

AbstractThe retinoic acid-related orphan receptor α (RORα) is an orphan member of the subfamily 1 of nuclear hormone receptors. No X-ray structure of RORα has been described so far, and no ligand has been identified. We describe the first crystal structure of the ligand binding domain (LBD) of RORα, at 1.63 Å resolution. This structure revealed a ligand present in the ligand binding pocket (LBP), which was identified by X-ray crystallography as cholest-5-en-3β-ol (cholesterol). Moreover, RORα transcriptional activity could be modulated by changes in intracellular cholesterol level or mutation of residues involved in cholesterol binding. These findings suggest that RORα could play a key role in the regulation of cholesterol homeostasis and thus represents an important drug target in cholesterol-related diseases