title: Structure-dependent binding and activation of perfluorinated compounds on human peroxisome proliferator-activated receptor γ.
abstract: 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 as hPPARγ agonists, and their potency correlated with their binding affinity with hPPARγ-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.
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, 18 Shuangqing Road, Beijing 100085, China; College of Life Science, Dezhou University, Dezhou 253023, China.
authors.forename: Lianying
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, 18 Shuangqing Road, Beijing 100085, China.
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, 18 Shuangqing Road, Beijing 100085, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wan
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, 18 Shuangqing Road, Beijing 100085, China. Electronic address: LHGuo@rcees.ac.cn.
authors.forename: Liang-Hong
authors.initials: LH
authors.lastname: Guo
mesh_terms: D001667:Binding, Competitive / Q000187:drug effects; D002264:Carboxylic Acids / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002942:Circular Dichroism; D004396:Coloring Agents; D005466:Fluorocarbons / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D008958:Models, Molecular; D047495:PPAR gamma / Q000187:drug effects* / Q000235:genetics; D047492:Peroxisome Proliferator-Activated Receptors / Q000187:drug effects*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts; D013844:Thiazoles; D014162:Transfection
chemical_list: D002264:Carboxylic Acids; D004396:Coloring Agents; D005466:Fluorocarbons; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue
keywords: Activation potency; Ligand binding assay; Molecular docking; PARγ; Perfluorinated compounds; Structure-dependent