title: Gaba receptor insecticide non-competitive antagonists may bind at allosteric modulator sites.
abstract: 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.
authors.affiliation: Chemistry, Materials, and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, California 94550, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Law
authors.forename: Felice C
authors.initials: FC
authors.lastname: Lightstone
mesh_terms: D000495:Allosteric Site / Q000187:drug effects*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D003198:Computer Simulation; D007306:Insecticides / Q000494:pharmacology*; D008956:Models, Chemical; D008961:Models, Structural; D021122:Protein Subunits; D011963:Receptors, GABA-A / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology*
chemical_list: D007306:Insecticides; D021122:Protein Subunits; D011963:Receptors, GABA-A