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J. Biol. Chem., Vol. 282, Issue 18, 13648-13655, May 4, 2007

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Crystal Structure of the T877A Human Androgen Receptor Ligand-binding Domain Complexed to Cyproterone Acetate Provides Insight for Ligand-induced Conformational Changes and Structure-based Drug Design^*

Casey E. Bohl, Zengru Wu, Duane D. Miller, Charles E. Bell^¶, and James T. Dalton¹

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

Cyproterone acetate (CPA) is a steroidal antiandrogen used clinically in the treatment of prostate cancer. Compared with steroidal agonists for the androgen receptor (AR) (e.g. dihydrotestosterone, R1881), CPA is bulkier in structure and therefore seemingly incompatible with the binding pockets observed in currently available x-ray crystal structures of the AR ligand-binding domain (LBD). We solved the x-ray crystal structure of the human AR LBD bound to CPA at 1.8Å in the T877A variant, a mutation known to increase the agonist activity of CPA and therefore facilitate purification and crystal formation of the receptor·drug complex. The structure demonstrates that bulk from the 17-acetate group of CPA induces movement of the Leu-701 side chain, which results in partial unfolding of the C-terminal end of helix 11 and displacement of the loop between helices 11 and 12 in comparison to all other AR LBD crystal structures published to date. This structural alteration leads to an expansion of the AR binding cavity to include an additional pocket bordered by Leu-701, Leu-704, Ser-778, Met-780, Phe-876, and Leu-880. Further, we found that CPA invokes transcriptional activation in the L701A AR at low nanomolar concentrations similar to the T877A mutant. Analogous mutations in the glucocorticoid receptor (GR) and progesterone receptor were constructed, and we found that CPA was also converted into a potent agonist in the M560A GR. Altogether, these data offer information for structure-based drug design, elucidate flexible regions of the AR LBD, and provide insight as to how CPA antagonizes the AR and GR.

Received for publication, December 21, 2006 , and in revised form, February 20, 2007.

The atomic coordinates and structure factors (code 2Oz7) 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 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 should be addressed: Dept. of Pharmaceutics, Ohio State University, 500 W. 12th Ave., Columbus, OH 43210. Tel.: 614-688-3797; Fax: 614-292-7766; E-mail: dalton.1{at}osu.edu.

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