A surface on the androgen receptor that allosterically regulates coactivator binding
A surface on the androgen receptor that allosterically regulates coactivator binding
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DOI：
10.1073/pnas.0708036104
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发表时间：
2007-10-09
影响因子：
11.1
通讯作者：
Fletterick, Robert J.
中科院分区：
文献类型：
--
作者：
Estebanez-Perpina, Eva;Arnold, Alexander A.;Fletterick, Robert J.
目前抑制核受体（NR）活性的方法靶向激素结合口袋，但面临局限性。我们已经提出，抑制剂，结合到核受体表面，介导的受体的结合伴侣的组装，可能会克服这些限制。雄激素受体（AR）在前列腺癌中起着核心作用，但传统的抑制剂失去了作为癌症治疗的有效性，因为抗雄激素抗性通常会发展。我们进行了功能和X射线筛选，以确定结合AR表面和阻断AR激活功能2（AF-2）的辅激活因子结合的化合物。检测到四种化合物，其在溶液中阻断辅激活剂结合，IC 50约为50 μ M，并抑制细胞中的AF-2活性：三种非甾体类药物和甲状腺激素3，3 '，5-三碘甲腺乙酸。虽然化合物在AR表面的可视化显示AF-2的结合较弱，但最有效的抑制剂优先结合以前未知的称为结合功能（BF）-3的调节表面裂缝，这是前列腺癌和雄激素不敏感综合征突变的已知靶点。X-射线结构分析表明，3，3 '，5-三碘甲腺乙酸与BF-3的结合重塑了相邻的相互作用位点AF-2，以削弱辅激活因子的结合。形成BF-3的残基突变会抑制AR功能和AR AF-2活性。我们认为BF-3是一个以前未被认识到的变构调节位点，是体内AR活性所必需的，也是一个可能的药物靶点。
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.