2012年8月14日 訊 /生物谷BIOON/ --英國(guó)癌癥研究中心科學(xué)家揭示男性雄激素能刺激前列腺癌的生長(zhǎng)，研究還發(fā)現(xiàn)某些現(xiàn)有的藥物具有用來(lái)治療該疾病的前景,。經(jīng)常用激素療法治療前列腺癌,，靶向雄激素受體（AR），雄激素受體是一個(gè)大的蛋白質(zhì),，能控制細(xì)胞分裂信號(hào),，并在前列腺癌細(xì)胞中過(guò)度活躍。
AR依賴與其他一些蛋白質(zhì)如HSP90和P23相互作用來(lái)發(fā)揮功效,，HSP90和P23相互作用有助于AR折疊成其活性形式,。以前認(rèn)為P23和HSP90一起作用來(lái)激活A(yù)R，但這一最新研究成果顯示P23也能獨(dú)立地不依賴于HSP90來(lái)提高AR活性,。
最重要的,，這意味著，阻斷P23可能能有效的治療對(duì)HSP90抑制劑耐受的前列腺,，HSP90抑制劑正在實(shí)驗(yàn)對(duì)乳腺癌和前列腺癌是否有效,。該研究結(jié)果發(fā)表在Molecular Endocrinology雜志上。
早期認(rèn)為HSP90和P23是相輔相成的，但我們驚奇地發(fā)現(xiàn)P23也能提高雄激素受體的活性,，即使我們使用了修改過(guò)的無(wú)法綁定HSP90的形式,。阻斷P23的藥物如雷公藤紅素能治療一些疾病如關(guān)節(jié)炎、哮喘等,，這意味著這項(xiàng)研究的成果已經(jīng)向臨床試驗(yàn)邁進(jìn)了一步。下一階段將是在實(shí)驗(yàn)室中測(cè)試這種藥物對(duì)前列腺癌細(xì)胞的影響,。（生物谷：Bioon.com）
編譯自：Scientists solve key piece of prostate cancer puzzle
doi:10.1210/me.2011-1281
PMC:
PMID:
Allosteric Conversation in the Androgen Receptor Ligand-Binding Domain Surfaces
Solène Grosdidier*, Laia R. Carbó*, Víctor Buzón, Greg Brooke, Phuong Nguyen, John D. Baxter§, Charlotte Bevan, Paul Webb, Eva Estébanez-Perpi?á** and Juan Fernández-Recio**
Androgen receptor (AR) is a major therapeutic target that plays pivotal roles in prostate cancer (PCa) and androgen insensitivity syndromes. We previously proposed that compounds recruited to ligand-binding domain (LBD) surfaces could regulate AR activity in hormone-refractory PCa and discovered several surface modulators of AR function. Surprisingly, the most effective compounds bound preferentially to a surface of unknown function [binding function 3 (BF-3)] instead of the coactivator-binding site [activation function 2 (AF-2)]. Different BF-3 mutations have been identified in PCa or androgen insensitivity syndrome patients, and they can strongly affect AR activity. Further, comparison of AR x-ray structures with and without bound ligands at BF-3 and AF-2 showed structural coupling between both pockets. Here, we combine experimental evidence and molecular dynamic simulations to investigate whether BF-3 mutations affect AR LBD function and dynamics possibly via allosteric conversation between surface sites. Our data indicate that AF-2 conformation is indeed closely coupled to BF-3 and provide mechanistic proof of their structural interconnection. BF-3 mutations may function as allosteric elicitors, probably shifting the AR LBD conformational ensemble toward conformations that alter AF-2 propensity to reorganize into subpockets that accommodate N-terminal domain and coactivator peptides. The induced conformation may result in either increased or decreased AR activity. Activating BF-3 mutations also favor the formation of another pocket (BF-4) in the vicinity of AF-2 and BF-3, which we also previously identified as a hot spot for a small compound. We discuss the possibility that BF-3 may be a protein-docking site that binds to the N-terminal domain and corepressors. AR surface sites are attractive pharmacological targets to develop allosteric modulators that might be alternative lead compounds for drug design.
