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J. Biol. Chem., Vol. 280, Issue 45, 37747-37754, November 11, 2005

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Structural Basis for Accommodation of Nonsteroidal Ligands in the Androgen Receptor^*

Casey E. Bohl, Duane D. Miller, Jiyun Chen, Charles E. Bell¶1, and James T. Dalton2

From the Division of Pharmaceutics, College of Pharmacy and ^¶Department of Molecular and Cellular Biochemistry, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio 43210 and Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, Memphis, Tennessee 38163

The mechanism by which the androgen receptor (AR) distinguishes between agonist and antagonist ligands is poorly understood. AR antagonists are currently used to treat prostate cancer. However, mutations commonly develop in patients that convert these compounds to agonists. Recently, our laboratory discovered selective androgen receptor modulators, which structurally resemble the nonsteroidal AR antagonists bicalutamide and hydroxyflutamide but act as agonists for the androgen receptor in a tissue-selective manner. To investigate why subtle structural changes to both the ligand and the receptor (i.e. mutations) result in drastic changes in activity, we studied structure-activity relationships for nonsteroidal AR ligands through crystallography and site-directed mutagenesis, comparing bound conformations of R-bicalutamide, hydroxyflutamide, and two previously reported nonsteroidal androgens, S-1 and R-3. These studies provide the first crystallographic evidence of the mechanism by which nonsteroidal ligands interact with the wild type AR. We have shown that changes induced to the positions of Trp-741, Thr-877, and Met-895 allow for ligand accommodation within the AR binding pocket and that a water-mediated hydrogen bond to the backbone oxygen of Leu-873 and the ketone of hydroxyflutamide is present when bound to the T877A AR variant. Additionally, we demonstrated that R-bicalutamide stimulates transcriptional activation in AR harboring the M895T point mutation. As a whole, these studies provide critical new insight for receptor-based drug design of nonsteroidal AR agonists and antagonists.

Received for publication, July 11, 2005

^* This work was supported by National Institutes of Health Grants R01 DK59800 and R01 DK065227. 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 To whom correspondence may be addressed. E-mail: bell.489{at}osu.edu. ² To whom correspondence may be addressed. E-mail: dalton.1{at}osu.edu.

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