{"title":"gabazine (SR-95531)与纹状线虫GABA受体相互作用的结构研究。","authors":"Yuki Fujie, Genyan Liu, Fumiyo Ozoe, Yoshihisa Ozoe","doi":"10.1584/jpestics.D22-007","DOIUrl":null,"url":null,"abstract":"<p><p>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 (<i>Laodelphax striatellus</i>) 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.</p>","PeriodicalId":16712,"journal":{"name":"Journal of Pesticide Science","volume":"47 2","pages":"78-85"},"PeriodicalIF":1.5000,"publicationDate":"2022-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/50/d2/jps-47-2-D22-007.PMC9184248.pdf","citationCount":"0","resultStr":"{\"title\":\"Structural insights into the interaction between gabazine (SR-95531) and <i>Laodelphax striatellus</i> GABA receptors.\",\"authors\":\"Yuki Fujie, Genyan Liu, Fumiyo Ozoe, Yoshihisa Ozoe\",\"doi\":\"10.1584/jpestics.D22-007\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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 (<i>Laodelphax striatellus</i>) 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.</p>\",\"PeriodicalId\":16712,\"journal\":{\"name\":\"Journal of Pesticide Science\",\"volume\":\"47 2\",\"pages\":\"78-85\"},\"PeriodicalIF\":1.5000,\"publicationDate\":\"2022-05-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/50/d2/jps-47-2-D22-007.PMC9184248.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Pesticide Science\",\"FirstCategoryId\":\"97\",\"ListUrlMain\":\"https://doi.org/10.1584/jpestics.D22-007\",\"RegionNum\":4,\"RegionCategory\":\"农林科学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"ENTOMOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Pesticide Science","FirstCategoryId":"97","ListUrlMain":"https://doi.org/10.1584/jpestics.D22-007","RegionNum":4,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ENTOMOLOGY","Score":null,"Total":0}
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.
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.