State Key Joint Laboratory of ESPC, School of Environment, Tsinghua University, Beijing 100084, China.
State Key Joint Laboratory of ESPC, School of Environment, Tsinghua University, Beijing 100084, China.
Environ Pollut. 2019 Dec;255(Pt 1):113193. doi: 10.1016/j.envpol.2019.113193. Epub 2019 Sep 7.
Phthalate esters (PAEs), as widely used plasticizers, have been concerned for their possible disruption of estrogen functions via binding to and activating the transcription of estrogen receptors (ERs). Nevertheless, the computational interpretation of the mechanism of ERs activities modulated by PAEs at the molecular level is still insufficient, which hinders the reliable screening of the ERs-active PAEs with high speed and high throughput. To bridge the gap, the in silico simulations considering the effects of coactivators were accomplished to explore the molecular mechanism of action for the purpose of predicting the estrogenic potencies of PAEs. The transcriptional activation functions of human ERα (hERα) modulated by PAEs is predicted via the simulations including binding interaction of PAEs and hERα, conformational changes of PAEs-hERα complexes and recruitment of coactivators. Molecular insight into the diverse estrogen mechanism of action among PAEs with regard to hERα agonists and selective estrogen receptor modulators (SERMs) is provided. Agonist-modulated conformational change of hERα leads to the optimal exposure of its Activation Function 2 (AF-2) surface which, in turn, facilitates the recruitment of coactivators, therefore promoting the transcriptional activation functions of hERα. Conversely, binding interaction of hERα with SERMs among PAEs leads to the conformational change with blocked AF-2 surface, thus preventing the recruitment of coactivators and consequently inhibiting the AF-2 activity. The two-hybrid recombinant yeast is experimentally used for verification. The established in silico evaluation methodology exhibits great promise to speed up the prediction of chemicals which work as hERα agonist or SERMs.
邻苯二甲酸酯（PAEs）作为广泛使用的增塑剂，由于其与雌激素受体（ERs）结合并激活转录，可能会破坏雌激素功能而受到关注。然而，在分子水平上，PAEs 调节 ERs 活性的机制的计算解释仍然不足，这阻碍了对具有高速度和高通量的 ERs 活性 PAEs 的可靠筛选。为了弥补这一差距，完成了考虑共激活剂影响的计算模拟，以探索 PAEs 作用的分子机制，目的是预测 PAEs 的雌激素潜力。通过包括 PAEs 与 hERα 的结合相互作用、PAEs-hERα 复合物的构象变化和共激活剂的募集在内的模拟来预测 PAEs 对人 ERα（hERα）的转录激活功能。提供了关于 hERα 激动剂和选择性雌激素受体调节剂（SERMs）的 PAEs 之间不同雌激素作用机制的分子见解。激动剂调节的 hERα 构象变化导致其激活功能 2（AF-2）表面的最佳暴露，进而促进共激活剂的募集，从而促进 hERα 的转录激活功能。相反，PAEs 中 hERα 与 SERMs 的结合相互作用导致构象变化和 AF-2 表面被封锁，从而阻止共激活剂的募集并抑制 AF-2 活性。使用双杂交重组酵母进行实验验证。所建立的计算评估方法有望加快对作为 hERα 激动剂或 SERMs 的化学物质的预测。
