The environmental endocrine disruptor p-nitrophenol interacts with FKBP51, a positive regulator of androgen receptor and inhibits androgen receptor signaling in human cells.
The environmental endocrine disruptor p-nitrophenol interacts with FKBP51, a positive regulator of androgen receptor and inhibits androgen receptor signaling in human cells.
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DOI：
10.1016/j.jhazmat.2015.12.045
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发表时间：
2016-04
影响因子：
13.6
通讯作者：
Dan Wu;X. Tao;Zhi-peng Chen;Jian-Ting Han;W. Jia;Ning Zhu;Xiangkai Li;Zhiping Wang;Yongxing He
中科院分区：
文献类型：
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作者：
Dan Wu;X. Tao;Zhi-peng Chen;Jian-Ting Han;W. Jia;Ning Zhu;Xiangkai Li;Zhiping Wang;Yongxing He
化合物对硝基苯酚具有抗雄激素活性，容易成为人为污染物，对环境和人类健康构成威胁。以往的研究表明，对硝基苯酚的抗雄激素作用机制复杂，可能涉及AR信号通路中的多个成分，但对硝基苯酚抑制AR信号转导的分子细节尚不十分清楚。在此，我们研究了对硝基苯酚与AR正性调节剂FKBP51的FK1结构域的微摩尔亲和力，并对FK1结构域的结构分析表明，对硝基苯酚占据了对AR活性增强至关重要的疏水FK1区域。分子动力学模拟表明，对硝基苯酚稳定地结合在FK1口袋上，参与结合的热点残基主要是疏水的，并与AR相互作用部位重叠。此外，我们还发现对硝基苯酚可能通过下调AR激活的下游基因的表达水平来抑制人前列腺癌细胞的雄激素依赖性生长。综上所述，我们的数据表明，对硝基苯酚至少部分地通过阻断AR与其正向调节因子FKBP51之间的相互作用来抑制AR信号通路。我们相信，我们的发现可以为评估对硝基苯酚的潜在健康影响提供新的指导方针。
The compoundp-nitrophenol, which shows the anti-androgenic activity, can easily become anthropogenic pollutants and pose a threat to the environment and human health. Previous work indicates that the anti-androgenic mechanism ofp-nitrophenol is complex and may involve several components in the AR signaling pathway, but the molecular details of howp-nitrophenol inhibits AR signaling are still not quite clear. Here, we characterizedp-nitrophenol binds to the FK1 domain of an AR positive regulator FKBP51 with micromolar affinity and structural analysis of FK1 domain in complex withp-nitrophenol revealed thatp-nitrophenol occupies a hydrophobic FK1 pocket that is vital for AR activity enhancement. Molecular dynamics simulation indicated thatp-nitrophenol is stably bound to the FK1 pocket and the hotspot residues that involvedp-nitrophenol binding are mainly hydrophobic and overlap with the AR interaction site. Furthermore, we showed thatp-nitrophenol inhibits the androgen-dependent growth of human prostate cancer cells, possibly through down-regulating the expression levels of AR activated downstream genes. Taken together, our data suggests thatp-nitrophenol suppresses the AR signaling pathway at least in part by blocking the interaction between AR and its positive regulator FKBP51. We believe that our findings could provide new guidelines for assessing the potential health effects ofp-nitrophenol.