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Homology modeling and docking study of diamondback moth ryanodine receptor reveals the mechanisms for channel activation, insecticide binding and resistance

机译:菱形蛾卤代胺受体的同源造型和对接研究揭示了通道激活,杀虫剂结合和抗性的机制

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摘要

BACKGROUND Diamide insecticides, including phthalic and anthranilic diamides, target insect ryanodine receptors (RyRs) and cause misregulation of calcium signaling in insect muscles and neurons. Several resistance mutations have been reported to reduce the efficacy of the diamides, but the exact binding sites and mechanism of resistance mutations are not clear. RESULTS The recent breakthrough in structural studies of mammalian RyRs has deepened our understanding of these giant calcium-release channels, but structural information about insect RyRs is still scarce. The only reported high-resolution structure is from the N-terminal domain of diamondback moth (DBM) RyR determined by our group. Here, we generate several homology models of full-length DBM RyR representing different functional states and dock the diamide insecticides into the structural models using Schrodinger software. These models reveal the specific structural features, activation mechanism, structural difference between functional states, ligand-binding sites and insecticide-binding sites of DBM RyR. By comparing the structures of wild-type and insecticide-resistant mutants, we propose a model depicting how the mutations affect the insecticide binding. We also identify the key difference between mammalian and insect RyRs that may explain the species-specific binding properties of diamides. CONCLUSION The binding sites for three activators Ca2+, ATP and caffeine, and regulator ryanodine are conserved in insect and mammalian RyRs, but the binding site for diamide insecticides is species-specific. The phthalic and anthranilic diamides have distinct binding properties in DBM, which can be interfered by resistance mutations located in the transmembrane region. (c) 2019 Society of Chemical Industry
机译:背景技术酰胺杀虫剂,包括邻苯二甲酸和蒽酰胺,靶昆虫卤代胺受体(Ryrs)并导致昆虫肌肉和神经元中的钙信号传导的误解。据报道,据报道了几种电阻突变降低了酰胺的功效,但是抗性突变的确切结合位点并不清楚。结果哺乳动物Ryrs结构研究中最近的突破深化了我们对这些巨型钙释放渠道的理解,但有关昆虫Ryrs的结构信息仍然稀缺。唯一报告的高分辨率结构来自我们组确定的菱形壁垒(DBM)RYR的N末端域。在这里,我们生成几种全长DBMRγ的同源模型,代表不同的功能状态,并使用Schrodinger软件将酰胺杀虫剂停放到结构模型中。这些模型揭示了DBM Ryr的功能状态,配体结合位点和杀虫剂结合位点之间的特定结构特征,活化机制,结构差异。通过比较野生型和抗虫剂抗突变体的结构,我们提出了一种模型,描绘了突变如何影响杀虫剂结合。我们还确定了哺乳动物和昆虫Rγ之间的关键差异,可以解释酰胺的特异性结合特性。结论三种活化剂CA2 +,ATP和咖啡因,ATP和咖啡因,和调节器瑞那胺的结合位点在昆虫和哺乳动物RYR中保守,但酰胺杀虫剂的结合位点是特异性的。邻苯二甲酸和蒽酰胺在DBM中具有明显的结合性质,其可以通过位于跨膜区域中的电阻突变干扰。 (c)2019年化学工业协会

著录项

  • 来源
    《Pest Management Science》 |2020年第4期|共13页
  • 作者单位

    Tianjin Univ Sch Pharmaceut Sci &

    Technol Collaborat Innovat Ctr Chem Sci &

    Engn Tianjin Key Lab Modern Drug Delivery &

    High Effic Tianjin 300072 Peoples R China;

    Tianjin Univ Sch Pharmaceut Sci &

    Technol Collaborat Innovat Ctr Chem Sci &

    Engn Tianjin Key Lab Modern Drug Delivery &

    High Effic Tianjin 300072 Peoples R China;

    Nanjing Univ Chinese Med Affiliated Hosp Integrated Tradit Chinese &

    Weste Key Lab Drug Targets &

    Drug Leads Degenerat Dis Nanjing Jiangsu Peoples R China;

    Tianjin Univ Sch Pharmaceut Sci &

    Technol Collaborat Innovat Ctr Chem Sci &

    Engn Tianjin Key Lab Modern Drug Delivery &

    High Effic Tianjin 300072 Peoples R China;

  • 收录信息
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 植物保护;
  • 关键词

    ryanodine receptor; diamide insecticide; diamondback moth; resistance; homology model; molecular docking;

    机译:瑞尼诺受体;酰胺杀虫剂;菱形蛾;抗性;同源性模型;分子对接;
  • 入库时间 2022-08-20 06:08:50

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