The Effect of Structural Diversity on Ligand Specificity and Resulting Signaling Differences of Estrogen Receptor alpha
The Effect of Structural Diversity on Ligand Specificity and Resulting Signaling Differences of Estrogen Receptor alpha
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结构多样性对配体特异性的影响以及由此产生的雌激素受体α信号差异
DOI：
10.1021/acs.chemrestox.8b00338
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发表时间：
2019
影响因子：
4.1
通讯作者：
Zhang Ai Qian
中科院分区：
文献类型：
--
作者：
Xue Qiao;Liu Xian;Liu Xiu Chang;Pan Wen Xiao;Fu Jian Jie;Zhang Ai Qian
许多化学物质通过与雌激素受体α（ERα）的配体结合域直接相互作用的受体结合机制发挥雌激素样内分泌干扰作用。然而，不仅它们与ERα的结合亲和力，而且它们对特定细胞和组织功能的干扰也明显不同。在这方面，已观察到三种代表性雌激素化学品（己烯雌酚（DES）、双酚A（BPA）和二芳基丙腈（DPN））（具有非常相似结构的众所周知的ERα激动剂）之间的显著调节差异。采用分子动力学模拟方法研究了相似的雌激素类化合物诱导不同调节效应的机制。DES诱导的H9-H10环的12 π运动显著扩大AF-2结构域的负静电势表面，这与激动剂的过度调节作用一致。相比之下，BPA和DPN诱导的3次运动对应于化学物质的低调节作用。交叉相关分析表明，AF-2结构域不同的ERα运动和表面特征是由激动剂不同的结合方式引起的。此外，只有具有雌激素样大小和柔性的疏水DES具有-23.47 kcal/mol结合自由能的高结合亲和力。DPN中的亲水基团和BPA的小分子尺寸都大大降低了激动剂的结合能力，它们的结合自由能分别只有−12.43 kcal/mol和−11.82 kcal/mol。我们的研究表明，类似的化学物质与ERα的相互作用不同，诱导不同的变构效应，这解释了观察到的调节多样性。
Numerous chemicals have been reported to exert estrogen-like endocrine disrupting effects via a receptor binding mechanism that directly interacts with the ligand binding domain of estrogen receptor α (ERα). However, not only their binding affinities to ERα but also their interference in specific cell and tissue functions are clearly different. In this regard, significant regulation differences among three representative estrogenic chemicals (diethylstilbestrol (DES), bisphenol A (BPA), and diarylpropionitrile (DPN)), well-known ERα agonists with very similar structures, have been observed. Molecular dynamics simulation is used to explore the underlying mechanism of different regulation effects induced by the similar estrogen-like chemicals. The DES-induced 12 Å motion of the H9–H10 loop markedly expands the negative electrostatic potential surface of the AF-2 domain, which is consistent with the over-regulation effect of the agonist. In comparison, the 3 Å motion induced by BPA and DPN corresponds to the low-regulation effect of the chemicals. Cross-correlation analysis indicates that the different ERα motions and resulting surface feature of AF-2 domain are brought by the distinguished binding modes of the agonists. Moreover, only hydrophobic DES with estrogen-like size and flexibility has a high binding affinity of −23.47 kcal/mol binding free energy. Both the hydrophilic group in DPN and the small molecular size of BPA dramatically decrease the agonist binding ability, and their binding free energies are only −12.43 kcal/mol and −11.82 kcal/mol, respectively. Our study demonstrates that similar chemicals interact differently with ERα and induce different allosteric effects, which explains the observed regulation diversity.