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J. Biol. Chem., Vol. 280, Issue 9, 8060-8068, March 4, 2005

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The Molecular Mechanisms of Coactivator Utilization in Ligand-dependent Transactivation by the Androgen Receptor^*

Eva Estébanez-Perpiñá, Jamie M. R. Moore, Ellena Mar, Edson Delgado-Rodrigues¶, Phuong Nguyen¶, John D. Baxter¶||, Benjamin M. Buehrer**, Paul Webb¶, Robert J. Fletterick, and R. Kiplin Guy

From the Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143, the Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California, San Francisco, California 94143, the ^¶Metabolic Research Unit and Diabetes Center, University of California, San Francisco, California 94143, and ^**Karo Bio USA, Durham, North Carolina 27703

Androgens drive sex differentiation, bone and muscle development, and promote growth of hormone-dependent cancers by binding the nuclear androgen receptor (AR), which recruits coactivators to responsive genes. Most nuclear receptors recruit steroid receptor coactivators (SRCs) to their ligand binding domain (LBD) using a leucine-rich motif (LXXLL). AR is believed to recruit unique coactivators to its LBD using an aromatic-rich motif (FXXLF) while recruiting SRCs to its N-terminal domain (NTD) through an alternate mechanism. Here, we report that the AR-LBD interacts with both FXXLF motifs and a subset of LXXLL motifs and that contacts with these LXXLL motifs are both necessary and sufficient for SRC-mediated AR regulation of transcription. Crystal structures of the activated AR in complex with both recruitment motifs reveal that side chains unique to the AR-LBD rearrange to bind either the bulky FXXLF motifs or the more compact LXXLL motifs and that AR utilizes subsidiary contacts with LXXLL flanking sequences to discriminate between LXXLL motifs.

Received for publication, June 23, 2004 , and in revised form, November 2, 2004.

The atomic coordinates and structure factors (codes 1T63, 1T5Z, 1T65, and 1XJ7) 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 the Prostate Cancer Foundation, by National Institutes of Health Grants DK58080 (to R. J. F. and R. K. G.) DK51281 (to J. D. B.), and CA8952 (to E. E.-P.) and by Department of Defense Grants DAMD17-01-1-0188 (to J. M. R. M.) and PC030607 (to P. W.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. SI.

^|| Has proprietary interests in, and serves as a consultant and Deputy Director to, Karo Bio AB, which has commercial interests in this area of research.

Present address, Karo Bio AB, Halsovagen, S-141, 57 Huddinge, Sweden.

To whom correspondence should be addressed: Dept. of Pharmaceutical Chemistry, University of California, 600 16th St., San Francisco, CA 94143. Tel.: 415-502-7051; Fax: 415-514-0689; E-mail: rguy{at}cgl.ucsf.edu.

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