The Effect of Structural Diversity on Ligand Specificity and Resulting Signaling Differences of Estrogen Receptor alpha

CORC > 生态环境研究中心 > 中国科学院生态环境研究中心 > 环境化学与生态毒理学国家重点实验室

	The Effect of Structural Diversity on Ligand Specificity and Resulting Signaling Differences of Estrogen Receptor alpha
	Xue, Qiao ; Liu, Xian ; Liu, Xiu-Chang ; Pan, Wen-Xiao ; Fu, Jian-Jie ; Zhang, Ai-Qian
刊名	CHEMICAL RESEARCH IN TOXICOLOGY
	2019-06
卷号	32 期号:6 页码:1002-1013
ISSN号	0893-228X
英文摘要	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 alpha (ER alpha). However, not only their binding affinities to ER alpha 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 ER alpha 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 angstrom 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 A motion induced by BPA and DPN corresponds to the low-regulation effect of the chemicals. Cross-correlation analysis indicates that the different ER alpha 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 ER alpha and induce different allosteric effects, which explains the observed regulation diversity.
内容类型	期刊论文
源URL	[http://ir.rcees.ac.cn/handle/311016/43038]
专题	生态环境研究中心_环境化学与生态毒理学国家重点实验室
作者单位	1.Chinese Acad Sci, State Key Lab Environm Chem & Ecotoxicol, Res Ctr Ecoenvironm Sci, Beijing 100085, Peoples R China 2.Univ Chinese Acad Sci, Coll Resources & Environm, Beijing 100049, Peoples R China 3.Jianghan Univ, Inst Environm & Hlth, Wuhan 430056, Hubei, Peoples R China
推荐引用方式 GB/T 7714	Xue, Qiao,Liu, Xian,Liu, Xiu-Chang,et al. The Effect of Structural Diversity on Ligand Specificity and Resulting Signaling Differences of Estrogen Receptor alpha[J]. CHEMICAL RESEARCH IN TOXICOLOGY,2019,32(6):1002-1013.
APA	Xue, Qiao,Liu, Xian,Liu, Xiu-Chang,Pan, Wen-Xiao,Fu, Jian-Jie,&Zhang, Ai-Qian.(2019).The Effect of Structural Diversity on Ligand Specificity and Resulting Signaling Differences of Estrogen Receptor alpha.CHEMICAL RESEARCH IN TOXICOLOGY,32(6),1002-1013.
MLA	Xue, Qiao,et al."The Effect of Structural Diversity on Ligand Specificity and Resulting Signaling Differences of Estrogen Receptor alpha".CHEMICAL RESEARCH IN TOXICOLOGY 32.6(2019):1002-1013.