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研究报告

The comparative study on the estrogen activities of organophosphorus pesticides mediated by ERα and ERβ

基金项目：国家自然科学基金(No. 21107094);中央高校基本科研业务费专项;高等学校博士学科点专项科研基金(No.20110101120075)

摘要：雌激素受体(Estrogen Receptor, ER)ERα和ERβ能与雌激素特异性结合,它们在结构上的差异性可能影响与类雌激素的相互作用,这进而会影响其功能.因此,针对10种有机磷农药对ERα和ERβ的雌激素效应差异,采用分子对接方法比较分析了它们与ERα、ERβ相互作用的差异并筛选出与ERα和ERβ相互作用的最佳结合模式.结果发现,10种有机磷农药分子与ERα配体结合域(Ligand Binding Domain,LBD)精氨酸(Arg394)、赖氨酸(Lys449)、色氨酸(Trp393)形成氢键;而部分农药分子与ERβ LBD精氨酸(Arg346)、亮氨酸(Leu343)、赖氨酸(Lys401)形成氢键.有机磷农药配体与ERα LBD Arg394、Lys449、苯丙氨酸(Phe445)、脯氨酸(Pro324)、Leu387、谷氨酸(Glu353)、甘氨酸(Gly390)等存在疏水作用,与ERβ LBD氨基酸Arg346、Glu305、Leu343、蛋氨酸(Met336)、组氨酸(His279)、丙氨酸(Ala302)等存在疏水作用.采用量子化学从头算进一步分析了10种有机磷农药分子表面静电势的差异.研究发现,有机磷农药分子与ERα和ERβ受体不同的相互作用是导致雌激素效应差异的重要原因.

Abstract：The estrogen receptor (ER), ERα and ERβ can specifically bind with estrogens and their structural difference between ERα and ERβ may result in different interaction with xenoestrogens, consequently affecting their function. Ten organophosphorus pesticides were previously reported to exhibit distinct estrogenic activities towards ERα and ERβ. To investigate the estrogenic activity difference, the binding modes of ten organophosphorus pesticides to ERα ligand binding domain (LBD) and ERβ LBD were compared by molecular docking and the optimal binding mode was obtained. Ten organophosphorus pesticides form hydrogen bonds with residues Arg394, Lys449 and Trp393 of ERα LBD and with residues Arg346, Leu343, Lys401 of ERβ LBD. Hydrophobic interaction of ten pesticides was formed with residues Arg394, Lys449, Glu353, Phe445, Pro324, Leu387 and Gly390 of ERα, and with residues Arg346, Glu305, Leu343, Met336, His279 and Ala302 of ERβ. The molecular electrostatic potential of ten organophosphorus pesticides was analyzed by ab initio quantum mechanics method. The obtained results revealed that the difference in the interactions of ten organophosphorus pesticides with ERα and ERβ is an important factor on their different activities towards ERα and ERβ.