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J. Biol. Chem., Vol. 282, Issue 35, 25801-25816, August 31, 2007

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Modulation of Androgen Receptor Activation Function 2 by Testosterone and Dihydrotestosterone^*

Emily B. Askew, Robert T. Gampe, Jr.^¶, Thomas B. Stanley^¶, Jonathan L. Faggart^||, and Elizabeth M. Wilson^||**1

From the Curriculum in Toxicology, Laboratories for Reproductive Biology, ^**Lineberger Comprehensive Cancer Center, and the Departments of ^||Pediatrics and Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599 and ^¶Computational and Structural Sciences, Division of Molecular Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 27709

The androgen receptor (AR) is transcriptionally activated by high affinity binding of testosterone (T) or its 5-reduced metabolite, dihydrotestosterone (DHT), a more potent androgen required for male reproductive tract development. The molecular basis for the weaker activity of T was investigated by determining T-bound ligand binding domain crystal structures of wild-type AR and a prostate cancer somatic mutant complexed with the AR FXXLF or coactivator LXXLL peptide. Nearly identical interactions of T and DHT in the AR ligand binding pocket correlate with similar rates of dissociation from an AR fragment containing the ligand binding domain. However, T induces weaker AR FXXLF and coactivator LXXLL motif interactions at activation function 2 (AF2). Less effective FXXLF motif binding to AF2 accounts for faster T dissociation from full-length AR. T can nevertheless acquire DHT-like activity through an AR helix-10 H874Y prostate cancer mutation. The Tyr-874 mutant side chain mediates a new hydrogen bonding scheme from exterior helix-10 to backbone protein core helix-4 residue Tyr-739 to rescue T-induced AR activity by improving AF2 binding of FXXLF and LXXLL motifs. Greater AR AF2 activity by improved core helix interactions is supported by the effects of melanoma antigen gene protein-11, an AR coregulator that binds the AR FXXLF motif and targets AF2 for activation. We conclude that T is a weaker androgen than DHT because of less favorable T-dependent AR FXXLF and coactivator LXXLL motif interactions at AF2.

Received for publication, April 18, 2007 , and in revised form, June 25, 2007.

The atomic coordinates and structure factors (code 2q7I, 2q7j, 2Q7K, 2Q7L) 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 United States Public Health Service Grant NICHD HD16910 from the National Institutes of Health, NICHD Grant U54-HD35041 of the specialized Cooperative Centers Program in Reproductive Research of the National Institutes of Health, NCI Grant P01-CA77739 from the National Institutes of Health, and by Grant T32 ES007126 from the Curriculum in Toxicology, University of North Carolina, Chapel Hill. 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: Laboratories for Reproductive Biology, CB 7500, University of North Carolina, Chapel Hill, NC 27599-7500. Tel.: 919-966-5168; Fax: 919-966-2203; E-mail: emw{at}med.unc.edu.

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