1. Editor’s Highlight: Structure-Based Investigation on the Binding and Activation of Typical Pesticides With Thyroid Receptor
- Author
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Guonian Zhu, Jian Han, Dandan Xiang, Bingsheng Zhou, Qiangwei Wang, Tingting Yao, and Abou Donia Mohamed
- Subjects
0301 basic medicine ,Insecticides ,medicine.medical_specialty ,Protein Conformation ,Biosensing Techniques ,Endocrine Disruptors ,010501 environmental sciences ,Ligands ,Transfection ,Toxicology ,Risk Assessment ,01 natural sciences ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Hormone Antagonists ,Luciferases, Firefly ,Cell Line, Tumor ,Internal medicine ,medicine ,Animals ,Humans ,Pituitary Neoplasms ,Luciferase ,Atrazine ,Surface plasmon resonance ,0105 earth and related environmental sciences ,Binding Sites ,Thyroid hormone receptor ,Dose-Response Relationship, Drug ,Herbicides ,Ligand binding assay ,Thyroid Hormone Receptors beta ,Surface Plasmon Resonance ,Pesticide ,Fungicides, Industrial ,Rats ,Molecular Docking Simulation ,Kinetics ,030104 developmental biology ,Endocrinology ,chemistry ,Biochemistry ,Hormone receptor ,Procymidone ,Protein Binding ,Thyroid Hormone Receptors alpha - Abstract
A broad range of pesticides have been reported to interfere with the normal function of the thyroid endocrine system. However, the precise mechanism(s) of action has not yet been thoroughly elucidated. In this study, 21 pesticides were assessed for their binding interactions and the potential to disrupt thyroid homeostasis. In the GH3 luciferase reporter gene assays, 5 of the pesticides tested had agonistic effects in the order of procymidone > imidacloprid > mancozeb > fluroxypyr > atrazine. 11 pesticides inhibited luciferase activity of T3 to varying degrees, demonstrating their antagonistic activity. And there are 4 pesticides showed mixed effects when treated with different concentrations. Surface plasmon resonance (SPR) biosensor technique was used to directly measure the binding interactions of these pesticides to the human thyroid hormone receptor (hTR). 13 pesticides were observed to bind directly with TR, with a KD ranging from 4.80E-08 M to 9.44E-07 M. The association and disassociation of the hTR/pesticide complex revealed 2 distinctive binding modes between the agonists and antagonists. At the same time, a different binding mode was displayed by the pesticides showed mix agonist and antagonist activity. In addition, the molecular docking simulation analyses indicated that the interaction energy calculated by CDOCKER for the agonists and antagonists correlated well with the KD values measured by the surface plasmon resonance assay. These results help to explain the differences of the TR activities of these tested pesticides.
- Published
- 2017