Folding of Androgen Receptor-Coregulator Complex

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DESCRIPTION (provided by applicant): The androgen receptor is the cellular mediator of the male sex hormone testosterone and a key regulator in the development and progression of prostate cancer. Androgen receptor is unusual among the family of nuclear receptors in that its hormone independent AF-1 activity is the dominant gene transactivation function. AF-1 activity has been mapped to a region of the N-terminal domain. This domain contains interaction sites for numerous coactivators, corepressors, and other proteins. Despite the critical role of AF-1 in androgen receptor function and prostate cancer pathology, the structural basis of AF-1 activity, and more generally the function of the N-terminal androgen receptor domain remains unknown. We will define, express, purify and crystallize stable complexes of N-terminal androgen receptor domain fragments with partnering domains of a representative subset of fifty coregulator proteins such as SRC's and ARA's. Our proposal employs high-throughput robotic expression and purification systems to screen thousands of paired combinations of N-terminal receptor domain and coregulator fragments to discover synergistic folding domains for stable complexes. The structure of androgen receptor-coregulator complex will reveal interactions necessary to design the first Pharmaceuticals directed to the N-terminal receptor domain in controlling prostate cancer. The ability to antagonize androgen receptor activity with agents affecting the interaction of the N-terminal androgen receptor domain with steroid receptor coactivators is expected to inhibit metastatic invasion and proliferation of prostate cancer. The goal of our study will be to establish a discovery strategy to identify small organic compounds as antagonists of androgen receptor activity in prostate cancer tumors by disrupting critical interactions between the N-terminal domain of the androgen receptor and key coregulators.