Role of pocket flexibility in the modulation of estrogen receptor alpha by key residue arginine 394
Role of pocket flexibility in the modulation of estrogen receptor alpha by key residue arginine 394
复制标题
DOI：
10.1002/etc.389
复制
发表时间：
2011-02
影响因子：
4.1
通讯作者：
Yunsong Mu;Sufen Peng;A. Zhang;Lian-Sheng Wang
中科院分区：
文献类型：
--
作者：
Yunsong Mu;Sufen Peng;A. Zhang;Lian-Sheng Wang
雌二醇衍生物与雌二醇（E2）或雌二醇代谢物具有相似的结构，已被公认对野生动物和人类具有有害的健康影响。然而，在分子水平上的数据，这些化合物与生物靶点的相互作用仍然缺乏。本文中，使用灵活的对接方法来表征9种雌二醇衍生物与配体结合结构域中的雌激素受体α（ERα）的分子相互作用。所有配体都停靠在类固醇激素口袋的埋藏疏水腔中。此外，还通过逆转氨基酸精氨酸394以获得更好的配体-受体结合亲和力来鉴定活性位点的可塑性。最后，基于转基因酵母菌株的生物测定用于验证分子模拟的质量，因为它们的快速性和高灵敏度。实验结果的中位有效浓度（EC 50）值的对数值与计算的结合亲和力从分子对接，这描述了雌二醇衍生物和ER之间的相互作用模式的线性相关。所有化合物的雌激素活性，虽然或多或少低于E2，被证明具有高的严重的环境风险。考虑到配体结合口袋中的侧链灵活性，基于对人ERα的原理验证计算，报告了17α-乙基炔雌醇-3-环戊基醚与已知诱导的拟合构象变化高度显著相关，并保留了谷氨酸353和精氨酸394之间的强盐桥。Environ.毒理学. 2011;30：330-336。© 2010 SETAC
Estradiol derivatives, with similar structures as estradiol (E2) or estradiol metabolites, have been recognized to have detrimental health effects on wildlife and humans. However, data at the molecular level about interactions of these compounds with biological targets are still lacking. Herein, a flexible docking approach was used to characterize the molecular interaction of nine estradiol derivatives with estrogen receptor alpha (ERα) in the ligand‐binding domain. All ligands were docked in the buried hydrophobic cavity of the steroid hormone pocket. In addition, the plasticity of an active site was also identified by reversing amino acid arginine 394 for better ligand‐receptor binding affinity. Finally, bioassays based on genetically modified yeast strains were used to validate the quality of molecular simulation because of their rapidity and high sensitivity. The experimental findings about logarithm values of the median effective concentration (EC50) value had a linear correlation with computational binding affinity from molecular docking, which described a pattern of interaction between estradiol derivatives and ER. The estrogenic activity of all compounds, although more or less lower than E2, was proved to possess high severe environmental risks. Considering the sidechain flexibility in the ligand binding pocket, 17α‐ethylestradiol‐3‐cyclopentylether was reported to correlate highly significantly with known induced fit conformational changes based upon proof‐of‐principle calculations on human ERα with the preservation of a strong salt bridge between glutamic acid 353 and arginine 394. Environ. Toxicol. Chem. 2011;30:330–336. © 2010 SETAC