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J. Biol. Chem., Vol. 282, Issue 42, 30910-30919, October 19, 2007

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Structural Characterization of the Human Androgen Receptor Ligand-binding Domain Complexed with EM5744, a Rationally Designed Steroidal Ligand Bearing a Bulky Chain Directed toward Helix 12^*

Line Cantin, Frédérick Faucher¹, Jean-François Couture², Karine Pereira de Jésus-Tran, Pierre Legrand^¶3, Liviu C. Ciobanu, Yvon Fréchette, Richard Labrecque, Shankar Mohan Singh, Fernand Labrie, and Rock Breton⁴

From the Oncology and Molecular Endocrinology Research Center, Laval University Medical Center (CHUL) and Laval University, Québec G1V 4G2, Canada, the Ottawa Institute of Systems Biology, Ottawa K1H 8M5, Canada, and ^¶Synchroton-SOLEIL, 91192 Gif-sur-Yvette, France

Antiandrogens are commonly used to treat androgen-dependent disorders. The currently used drugs unfortunately possess very weak affinity for the human AR (hAR), thus indicating the need to develop new high-affinity steroidal antiandrogens. Our compounds are specially designed to impede repositioning of the mobile carboxyl-terminal helix 12, which blocks the ligand-dependent transactivation function (AF-2) located in the AR ligand-binding domain (ARLBD). Using crystal structures of the hARLBD, we first found that H12 could be directly reached from the ligand-binding pocket (LBP) by a chain positioned on the C18 atom of an androgen steroid nucleus. A set of 5-dihydrotestosterone-derived molecules bearing various C18 chains were thus synthesized and tested for their capacity to bind hAR and act as antagonists. Although most of those having very high affinity for hAR were agonists, several very potent antagonists were obtained, confirming the structural importance of the C18 chain. To understand the role of the C18 chain in their agonistic/antagonistic properties, the structure of the hARLBD complexed with one of these agonists, EM5744, was determined at a 1.65-Å resolution. We have identified new interactions involving Gln⁷³⁸, Met⁷⁴², and His⁸⁷⁴ that explain both the high affinity of this compound and the inability of its bulky chain to prevent the repositioning of H12. This structural information will be helpful to refine the structure of the chains placed on the C18 atom to obtain efficient H12-directed steroidal antiandrogens.

Received for publication, July 5, 2007 , and in revised form, August 1, 2007.

The atomic coordinates and structure factors (code 2PNU) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported in part by Endorecherche Inc. 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.

¹ Recipient of a doctoral scholarship provided by the Fonds de la Recherche en Santé du Québec.

² Present address: Ottawa Institute of Systems Biology, 451 Smyth Rd., Ottawa, Ontario K1H 8M5, Canada.

³ Present address: Synchrotron-SOLEIL, BP48 Saint Aubin, 91192 Gif-sur-Yvette, France.

⁴ To whom correspondence should be addressed: Centre de Recherche en Endocrinologie Moléculaire et Oncologique, Centre Hospitalier de l'Université Laval (CHUL), 2705, boul. Laurier, Ste-Foy (Qc) G1V 4G2, Canada. Tel.: 418-654-2296; Fax: 418-654-2761; E-mail: rock.breton{at}crchul.ulaval.ca.

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