Insecticide interactions with .GAMMA.-aminobutyric acid and nicotinic receptors: predictive aspects of structural models

Abstract

An insecticide binding site may be blocked by widely diverse chemicals, as with the g-aminobutyric acid receptor (GABAR), or accept only closely related compounds, as illustrated by the nicotinic acetylcholine (ACh) receptor (nAChR). The human GABAR b3-homopentamer resembles the insect receptor in sensitivity and specificity for noncompetitive antagonists (NCAs), prompting exhaustive site-directed mutagenesis (cysteine scanning), which pinpointed the critical active site as pore-facing residues Ala-2Ј, Thr-6Ј and Leu-9Ј and led to a binding site model which fits several classes of insecticidal NCAs. The nAChR agonist site was approached with an ACh binding protein (AChBP) by photoaffinity labeling and neonicotinoid docking. Chloropyridinyl chlorine contacts Ile-106/Met-116 and nitrogen is directed to Ile-118/Trp-147 via a solvent bridge(s). The guanidine/amidine plane undergoes p-stacking with Tyr-188, and the nitro/cyano pharmacophore interacts with Ser-189/Cys-190, thereby defining the binding pocket that models AChBP and possibly nAChR potency and selectivity.

Fipronil resistance in Sogatella furcifera: Molecular cloning and functional expression of wild-type and mutant RDL GABA receptor subunits

“…A2′, T6′, and L9′ (index number for the M2 membrane-spanning region) 3) are particularly important for their binding. [4][5][6] An A2′S mutation in M2 confers resistance to the cyclodienes in D. melanogaster. 7) In this study, the index number for the M2 membrane-spanning region was used to aid in the comparison of M2 mutations in the GABA receptors from various species.…”

3-(4-Hydroxybenzylidene)anabaseine: High-affinity ligand for Periplaneta americana nicotinic acetylcholine receptors

“…16,17) The discovery and subsequent crystal structure analyses of structural and functional surrogates of the agonist binding domain of nAChRs have been of great help in promoting understanding about the ligand recognition properties of the binding site at atomic resolution, 18,19) and knowledge of the neonicotinoid binding site of insect nAChRs has remarkably advanced. [20][21][22][23][24][25] In comparisons between ligand affinities for AChBPs from three molluskan species and those for Pa-nAChRs, it was observed that the addition of a hydroxyl group to the para-position of BA to give 6 led to 25-and 10-fold increases in affinity for LsAChBP and Pa-nAChRs, respectively, whereas the influence of this substitution was small for Aplysia californica (Ac)-and Bulinus truncates (Bt)-AChBP, indicating the similarity of PanAChRs to Ls-AChBP. 13) Pa-nAChRs are also similar to LsAChBP in terms of the markedly low affinity of 5 compared to 6; however, Pa-nAChRs are similar to Bt-AChBP in the effect of the ortho-methoxy group.…”

Toward deeper understanding of bioactive molecules for innovative crop protection

“…The first article is a review of the molecular prediction of insecticide binding sites in two important ionotropic receptors. 1 Recent advances in studies on actions of pesticides and bioactive molecules choline receptors (nAChRs). First, human b3 GABA receptors, which pharmacologically resemble insect GABA receptors, were used for exhaustive site-directed mutagenesis and ligand docking simulations, leading to novel conclusion that structurally diverse antagonists fit the same site in the receptor channel pore.…”