Structure-dependent binding and activation of perfluorinated compounds on human peroxisome proliferator-activated receptor gamma.
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Zhang L, Ren XM, Wan B, Guo LH
Structure-dependent binding and activation of perfluorinated compounds on human peroxisome proliferator-activated receptor gamma.
Toxicol Appl Pharmacol. 2014 Sep 15;279(3):275-83. doi: 10.1016/j.taap.2014.06.020. Epub 2014 Jul 3.
- PubMed ID
- 24998974 [ View in PubMed]
- 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 PPARalpha was activated by PFCs. However, the information on the binding interactions between PPARgamma and PFCs and subsequent alteration of PPARgamma activity is still limited and sometimes inconsistent. In the present study, in vitro binding of 16 PFCs to human PPARgamma ligand binding domain (hPPARgamma-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 hPPARgamma agonists, and their potency correlated with their binding affinity with hPPARgamma-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.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Capric acid Peroxisome proliferator-activated receptor gamma Protein Humans UnknownLigandDetails Oleic Acid Peroxisome proliferator-activated receptor gamma Protein Humans UnknownLigandDetails