A surface on the androgen receptor that allosterically regulates coactivator binding

被引:232
作者
Estebanez-Perpina, Eva
Arnold, Alexander A.
Nguyen, Phuong
Rodrigues, Edson Delgado
Mar, Ellena
Bateman, Raynard
Pallai, Peter
Shokat, Kevan M.
Baxter, John D. [1 ]
Guy, R. Kiplin
Webb, Paul
Fletterick, Robert J.
机构
[1] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA
[3] Univ Calif San Francisco, Dept Mol & Cellular Pharmacol, San Francisco, CA 94143 USA
[4] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA
[5] St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, Memphis, TN 38105 USA
[6] Bioblocks Inc, San Diego, CA 92121 USA
关键词
antagonist; high-throughput screening; regulatory surface; antiandrogens; nuclear receptors;
D O I
10.1073/pnas.0708036104
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Current approaches to inhibit nuclear receptor (NR) activity target the hormone binding pocket but face limitations. We have proposed that inhibitors, which bind to nuclear receptor surfaces that mediate assembly of the receptor's binding partners, might overcome some of these limitations. The androgen receptor (AR) plays a central role in prostate cancer, but conventional inhibitors lose effectiveness as cancer treatments because anti-androgen resistance usually develops. We conducted functional and x-ray screens to identify compounds that bind the AR surface and block binding of coactivators for AR activation function 2 (AF-2). Four compounds that block coactivator binding in solution with IC50 approximate to 50 mu M and inhibit AF-2 activity in cells were detected: three nonsteroidal antiinflammatory drugs and the thyroid hormone 3,3',5-triiodothyroacetic acid. Although visualization of compounds at the AR surface reveals weak binding at AF-2, the most potent inhibitors bind preferentially to a previously unknown regulatory surface cleft termed binding function (BF)-3, which is a known target for mutations in prostate cancer and androgen insensitivity syndrome. X-ray structural analysis reveals that 3,3',5-triiodothyroacetic acid binding to BF-3 remodels the adjacent interaction site AF-2 to weaken coactivator binding. Mutation of residues that form BF-3 inhibits AR function and AR AF-2 activity. We propose that BF-3 is a previously unrecognized allosteric regulatory site needed for AR activity in vivo and a possible pharmaceutical target.
引用
收藏
页码:16074 / 16079
页数:6
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