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J. Biol. Chem., Vol. 279, Issue 14, 14033-14038, April 2, 2004

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Crystal Structure of the Human ROR Ligand Binding Domain in Complex with Cholesterol Sulfate at 2.2 Å^*

Joerg Kallen, Jean-Marc Schlaeppi¶, Francis Bitsch¶, Isabelle Delhon||, and Brigitte Fournier||**

From the Discovery Technologies, Protein Structure Unit, the ^¶Discovery Technologies, Biomolecules Production Unit, and the ^||Arthritis and Bone Metabolism, Bone Metabolism Unit, Novartis Pharma AG, CH-4002 Basel, Switzerland

The retinoic acid-related orphan receptor (ROR) is an orphan member of the subfamily 1 of nuclear hormone receptors. Our recent structural and functional studies have led to the hypothesis that cholesterol or a cholesterol derivative is the natural ligand of ROR. We have now solved the x-ray crystal structure of the ligand binding domain of ROR in complex with cholesterol-3-O-sulfate following a ligand exchange experiment. In contrast to the 3-hydroxyl of cholesterol, the 3-O-sulfate group makes additional direct hydrogen bonds with three residues of the ROR ligand binding domain, namely NH-Gln²⁸⁹, NH-Tyr²⁹⁰, and NH1-Arg³⁷⁰. When compared with the complex with cholesterol, seven well ordered water molecules have been displaced, and the ligand is slightly shifted toward the hydrophilic part of the ligand binding pocket, which is ideally suited for interactions with a sulfate group. These additional ligand-protein interactions result in an increased affinity of cholesterol sulfate when compared with cholesterol, as shown by mass spectrometry analysis done under native conditions and differential scanning calorimetry. Moreover, mutational studies show that the higher binding affinity of cholesterol sulfate translates into an increased transcriptional activity of ROR. Our findings suggest that cholesterol sulfate could play a crucial role in the regulation of ROR in vivo.

Received for publication, January 12, 2004

The atomic coordinates and structure factors (code 1SOX) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brujswick, NJ (http://www.rcsb.org/).

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence may be addressed. E-mail: joerg.kallen{at}pharma.novartis.com. ^** To whom correspondence may be addressed. E-mail: brigitte.fournier{at}pharma.novartis.com.

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