Fujie Yuki, Liu Genyan, Ozoe Fumiyo, Ozoe Yoshihisa
Faculty of Life and Environmental Sciences, Shimane University, Matsue, Shimane 690-8504, Japan.
Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, Hubei 430205, People's Republic of China.
J Pestic Sci. 2022 May 20;47(2):78-85. doi: 10.1584/jpestics.D22-007.
γ-Aminobutyric acid receptors (GABARs) mediate fast inhibitory neurotransmission and are targets for insecticides. GABARs are composed of five subunits, the composition of which dictates the pharmacological characteristics of GABARs. Both competitive and noncompetitive GABAR antagonists can be used as insecticides. Gabazine is a potent competitive antagonist of mammalian α1β2γ2 GABARs; however, it is less potent against insect GABARs. To explore how gabazine interacts with GABARs, we examined whether the sensitivity of the small brown planthopper () RDL GABAR (LsRDLR) to gabazine is increased when its amino acid residues are substituted with α1β2γ2 GABAR residues. In the results, two of the generated mutants showed enhanced gabazine sensitivity. Docking simulations of gabazine using LsRDLR homology models and an α1β2γ2 GABAR cryo-EM structure revealed that the accommodation of gabazine into the "aromatic box" in the orthosteric site lowered the binding energy. This information may help in designing GABAR-targeting insecticides with novel modes of action.
γ-氨基丁酸受体（GABARs）介导快速抑制性神经传递，并且是杀虫剂的作用靶点。GABARs由五个亚基组成，其组成决定了GABARs的药理学特性。竞争性和非竞争性GABAR拮抗剂均可用作杀虫剂。gabazine是哺乳动物α1β2γ2 GABARs的强效竞争性拮抗剂；然而，它对昆虫GABARs的效力较低。为了探究gabazine如何与GABARs相互作用，我们检测了将小褐飞虱（）RDL GABAR（LsRDLR）的氨基酸残基用α1β2γ2 GABAR残基替换后，其对gabazine的敏感性是否增加。结果显示，所产生的两个突变体对gabazine的敏感性增强。使用LsRDLR同源模型和α1β2γ2 GABAR冷冻电镜结构对gabazine进行对接模拟，结果表明gabazine进入正构位点的“芳香盒”会降低结合能。这些信息可能有助于设计具有新型作用模式的靶向GABAR的杀虫剂。
