Structure-dependent binding and activation of perfluorinated compounds on human peroxisome proliferator-activated receptor γ.
Structure-dependent binding and activation of perfluorinated compounds on human peroxisome proliferator-activated receptor γ.
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DOI：
10.1016/j.taap.2014.06.020
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发表时间：
2014-09
影响因子：
3.8
通讯作者：
Lianying Zhang;Xiaomin Ren;B. Wan;Liang-Hong Guo
中科院分区：
文献类型：
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作者：
Lianying Zhang;Xiaomin Ren;B. Wan;Liang-Hong Guo
研究表明，全氟化合物（pfc）可通过激活过氧化物酶体增殖物激活受体（ppar）破坏啮齿动物的脂质代谢，甚至诱发癌症。一系列证据表明ppara被pfc激活。然而，关于PPARγ和pfc之间的结合相互作用以及随后的PPARγ活性改变的信息仍然有限，有时不一致。本研究研究了16种pfc与人PPARγ配体结合域（hpar γ- lbd）的体外结合及其对细胞受体的活性。结果表明，它们的结合亲和力与碳数和官能团密切相关。对于11种全氟羧酸（PFCAs），其结合亲和力随碳数从4到11而增加，然后略有下降。三种全氟磺酸（PFSAs）的结合亲和力比它们的PFCA对应物强。未检测到两种氟端粒醇（FTOHs）的结合。圆二铬光谱显示，PFC结合诱导了受体明显的结构变化。在使用瞬时转染的Hep G2细胞进行的双荧光素酶报告基因检测中，pfc可作为hppar γ激动剂，其效力与其与hppar γ- lbd的结合亲和力相关。分子对接表明，不同链长的PFCs与受体结合的几何形状不同，这可能是它们结合亲和力和转录活性差异的原因。
Perfluorinated compounds (PFCs) have been shown to disrupt lipid metabolism and even induce cancer in rodents through activation of peroxisome proliferator-activated receptors (PPARs). Lines of evidence showed that PPARα was activated by PFCs. However, the information on the binding interactions between PPARγ and PFCs and subsequent alteration of PPARγ activity is still limited and sometimes inconsistent. In the present study, in vitro binding of 16 PFCs to human PPARγ ligand binding domain (hPPARγ-LBD) and their activity on the receptor in cells were investigated. The results showed that the binding affinity was strongly dependent on their carbon number and functional group. For the eleven perfluorinated carboxylic acids (PFCAs), the binding affinity increased with their carbon number from 4 to 11, and then decreased slightly. The binding affinity of the three perfluorinated sulfonic acids (PFSAs) was stronger than their PFCA counterparts. No binding was detected for the two fluorotelomer alcohols (FTOHs). Circular dichroim spectroscopy showed that PFC binding induced distinctive structural change of the receptor. In dual luciferase reporter assays using transiently transfected Hep G2 cells, PFCs acted ashPPARγ agonists, and their potency correlated with their binding affinity withhPPARγ-LBD. Molecular docking showed that PFCs with different chain length bind with the receptor in different geometry, which may contribute to their differences in binding affinity and transcriptional activity.