Law Richard J, Lightstone Felice C
Chemistry, Materials, and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, California 94550, USA.
Int J Neurosci. 2008 May;118(5):705-34. doi: 10.1080/00207450701750216.
Results from several studies have shown that a series of chemically distinct insecticide compounds (picrotoxin, BIDN, TBPS, fipronil, lindane, EBOB, and alpha-endosulfan) affect GABA A receptor function. In this investigation, docking of this set of insecticides to the GABA receptor identified five potential binding sites. The lowest energy site was found within the base of the transmembrane bundle, interacting with M2 but not in the pore, and includes many of the residues previously experimentally implicated in insecticide binding. Many of the binding modes are suggestive of a non-competitive allosteric mechanism based on interruption of the channel gating mechanism rather than directly blocking the channel. The results also distinguished between isomers of hexachlorohexane (HCH), where gamma-HCH (lindane) binds more favorably than beta-HCH. The results suggest multiple sites for insecticide binding and may suggest further mutagenesis and labeling work to either confirm or rule out these findings.
多项研究结果表明，一系列化学性质不同的杀虫剂化合物（印防己毒素、BIDN、TBPS、氟虫腈、林丹、EBOB和α-硫丹）会影响GABA A受体功能。在本研究中，将这组杀虫剂与GABA受体进行对接，确定了五个潜在结合位点。能量最低的位点位于跨膜束基部，与M2相互作用但不在孔内，并且包含许多先前实验表明与杀虫剂结合有关的残基。许多结合模式表明存在一种非竞争性变构机制，其基于通道门控机制的中断，而非直接阻断通道。研究结果还区分了六氯环己烷（HCH）的异构体，其中γ-六氯环己烷（林丹）的结合比β-六氯环己烷更有利。这些结果表明杀虫剂结合存在多个位点，可能意味着需要进一步开展诱变和标记工作，以证实或排除这些发现。
