gabazine (SR-95531)与纹状线虫GABA受体相互作用的结构研究。

IF 1.5 4区 农林科学 Q2 ENTOMOLOGY Journal of Pesticide Science Pub Date : 2022-05-20 DOI:10.1584/jpestics.D22-007
Yuki Fujie, Genyan Liu, Fumiyo Ozoe, Yoshihisa Ozoe
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引用次数: 0

摘要

γ-氨基丁酸受体(gabar)介导快速抑制性神经传递,是杀虫剂的靶点。gabar由五个亚基组成,它们的组成决定了gabar的药理学特性。竞争性和非竞争性GABAR拮抗剂都可用作杀虫剂。Gabazine是一种有效的哺乳动物α1β2γ2 gabar的竞争性拮抗剂;然而,它对昆虫gabar的作用较弱。为了探究gabazine与GABARs的相互作用机制,我们检测了当小褐飞虱(Laodelphax striatellus) RDL GABAR (LsRDLR)的氨基酸残基被α1β2γ2 GABAR残基取代时,gabazine对gabazine的敏感性是否增加。结果显示,产生的两个突变体显示出增强的gabazine敏感性。利用LsRDLR同源模型和α1β2γ2 GABAR低温电镜结构对gabazine进行对接模拟,结果表明,gabazine被安置在正构位的“芳香盒子”中,降低了结合能。这些信息可能有助于设计具有新型作用模式的gabar靶向杀虫剂。
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Structural insights into the interaction between gabazine (SR-95531) and Laodelphax striatellus GABA receptors.

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 (Laodelphax striatellus) 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.

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来源期刊
Journal of Pesticide Science
Journal of Pesticide Science 农林科学-昆虫学
CiteScore
4.30
自引率
4.20%
发文量
28
审稿时长
18-36 weeks
期刊介绍: The Journal of Pesticide Science publishes the results of original research regarding the chemistry and biochemistry of pesticides including bio-based materials. It also covers their metabolism, toxicology, environmental fate and formulation.
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