Structural basis for antagonism and resistance of bicalutamide in prostate cancer
Structural basis for antagonism and resistance of bicalutamide in prostate cancer
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DOI：
10.1073/pnas.0500381102
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发表时间：
2005-04-26
影响因子：
11.1
通讯作者：
Dalton, JT
中科院分区：
文献类型：
--
作者：
Bohl, CE;Gao, WQ;Dalton, JT
前列腺癌是男性最常见的癌症。目前用于进行性雄激素依赖性前列腺癌的药物治疗选择是非甾体类抗雄激素比卡鲁胺，可作为单药治疗或与辅助去势或促黄体生成素释放激素超激动剂联合使用，以阻断内源性睾酮的合成。迄今为止，没有非甾体或拮抗剂结合的雄激素受体（AR）结构。我们以1.8埃分辨率解析了与R-比卡鲁胺结合的突变体W741 L AR配体结合结构域的X射线晶体结构。该突变赋予比卡鲁胺激动剂活性，可能与比卡鲁胺戒断综合征有关。三维结构表明，W741 L突变体中R-比卡鲁胺的B环位于与二氢睾酮结合的WT AR中Trp-741的吲哚环位置。了解R-比卡鲁胺的结合机制将为开发新的抗雄激素和选择性AR调节剂提供分子基础。
Carcinoma of the prostate is the most commonly diagnosed cancer in men. The current pharmacological treatment of choice for progressive androgen-dependent prostate cancer is the nonsteroidal antiandrogen, bicalutamide, either as monotherapy or with adjuvant castration or luteinizing hormone-releasing hormone superagonists to block the synthesis of endogenous testosterone. To date, no nonsteroidal or antagonist-bound androgen receptor (AR) structure is available. We solved the x-ray crystal structure of the mutant W741L AR ligand-binding domain bound to R-bicalutamide at 1.8-angstrom resolution. This mutation confers agonist activity to bicalutamide and is likely involved in bicalutamide withdrawal syndrome. The three-dimensional structure demonstrates that the B ring of R-bicalutamide in the W741L mutant is accommodated at the location of the indole ring of Trp-741 in the WT AR bound to dihydrotestosterone. Knowledge of the binding mechanism for R-bicalutamide will provide molecular rationale for the development of new antiandrogens and selective AR modulators.