2008 年 33 巻 1 号 p. 4-8
An insecticide binding site may be blocked by widely diverse chemicals, as with the γ-aminobutyric acid receptor (GABAR), or accept only closely related compounds, as illustrated by the nicotinic acetylcholine (ACh) receptor (nAChR). The human GABAR β3-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-2′, Thr-6′ and Leu-9′ 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 π-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.
