High-resolution insights into insecticide interactions with voltage-gated sodium channels

杀虫剂与电压门控钠通道相互作用的高分辨率见解

• 批准号: 10609839
• 负责人: KE DONG
• 金额: $ 37.7万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609839
• 关键词: Agonist; Applications Grants; Arthropod Vectors; Arthropods; Basic Science; Batrachotoxins; Beds; Binding Sites; Chemicals; Collaborations; Complex; Computer Models; Cryoelectron Microscopy; Culicidae; Development; Electrophysiology (science); Future; Genes; Goals; Grant; Insecta; Insecticide Resistance; Insecticides; Knowledge; Laboratories; Ligands; Modeling; Molecular; Molecular Mechanisms of Action; Monitor; Mutation; Nature; Neurotoxins; Potassium; Principal Investigator; Research; Resistance; Resistance development; Resolution; Series; Site; Sodium Channel; Sodium Channel Blockers; Structure; Toxic effect; Uncertainty; Vector-transmitted infectious disease; Veratridine; arthropod-borne; base; combat; human disease; insight; knock-down; pyrethroid; receptor; resistance mechanism; synthetic drug; three dimensional structure; vector control; vector transmission; voltage

Project Summary Voltage-gated sodium channels (Navs) are targets of a variety of natural neurotoxins and insecticides, including pyrethroids and sodium-channel-blocker insecticides (SCBIs). Pyrethroids are currently one of the most important and effective arsenals against mosquitoes and other arthropod vectors that transmit human diseases. SCBIs belong to a newer class of selective insecticides. A major challenge for effective vector control is global emergence of insecticide resistance. In particular, mutations in Nav genes confer a major form of resistance known as knockdown resistance (kdr). In the absence of 3-D structures of eukaryotic Navs in complex with pyrethroids or SCBIs, major uncertainties remain in understanding their interactions (including the nature of respective receptor sites) and kdr mechanisms. In this grant proposal, we take advantage of recent breakthroughs in the co-PI’s laboratory in the determination of the cryo-EM structures of several eukaryotic Navs. The availability of these Nav structures now promises an unprecedented new level of understanding of Nav interactions with insecticides and other neurotoxins. We propose to determine cryo-EM structures of Navs in complex with pyrethroids, SCBIs and three other neurotoxins and use these structures as a guide to conduct a comprehensive series of mutational, electrophysiological and computational modeling analyses of respective Nav-ligand interactions. Two specific aims of this renewal proposal are: 1) determine cryo-EM structures of eukaryotic Nav complexes with various pyrethroids to gain insights into the atomic mechanisms of pyrethroids and kdr, and 2) Investigate the mechanisms of Nav interactions with SCBIs (DCJW and metaflumizone), steroidal agonists (BTX and veratridine) and the alkylamide insecticide BTG 502. Results from this research will push our understanding of the molecular actions of pyrethroids, SCBIs and other neurotoxins to a new level, thereby facilitating the development of precision monitoring and management of insecticide resistance worldwide and discovery of new and safe Nav-targeting chemicals to combat global threats from arthropod disease-transmitting vectors.

项目摘要 电压门控钠通道（NAV）是多种天然神经毒素和杀虫剂的靶标，包括 拟除虫菊酯和钠通道阻滞剂杀虫剂（SCBIS）。拟除虫菊酯目前是最多的 针对传播人类疾病的蚊子和其他节肢动物载体的重要和有效的武器库。 SCBI属于一类新的选择性杀虫剂。有效矢量控制的主要挑战是全球 抗杀虫剂的出现。特别是，NAV基因中的突变会议会议的主要形式 称为敲低阻力（KDR）。在没有3-D结构的情况下，真核NAV与 拟除虫菊酯或SCBI，主要不确定性在理解它们的相互作用方面仍然存在（包括 在该赠款提案中，我们利用了最近的优势 Co-Pi实验室的突破，确定了几种真核NAV的冷冻EM结构。 这些NAV结构的可用性现在有望成为对NAV的前所未有的新水平 与杀虫剂和其他神经毒素的相互作用。我们建议确定NAV中的冷冻EM结构 与拟除虫菊酯，SCBI和其他三种神经毒素配合物，并使用这些结构作为指导 相对的全面系列突变，电生理和计算建模分析 NAV-配体相互作用。该更新建议的两个具体目的是：1）确定的冷冻EM结构 真核N​​AV与各种拟甲虫素的复合物，以洞悉拟除虫菊酯的原子机制 和KDR，以及2）研究与SCBIS（DCJW和Metaflumizone），类固醇相互作用的机制 激动剂（BTX和Veratridine）和烷基酰胺杀虫剂BTG 502。这项研究的结果将推动我们的 了解拟除虫菊酯，SCBI和其他神经毒素的分子作用，因此 促进全球抗杀虫剂抗性的精确监测和管理和管理 发现新的和安全的海军靶向化学物质，以应对节肢动物疾病传播的全球威胁 向量。

项目成果

Differential effects of TipE and a TipE-homologous protein on modulation of gating properties of sodium channels from Drosophila melanogaster.

• DOI: 10.1371/journal.pone.0067551
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Wang L;Nomura Y;Du Y;Dong K
• 通讯作者: Dong K

Sequence variations at I260 and A1731 contribute to persistent currents in Drosophila sodium channels.

I260 和 A1731 的序列变化导致果蝇钠通道中的持续电流

• DOI: 10.1016/j.neuroscience.2014.03.028
• 发表时间: 2014-05-30
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: Gao R;Du Y;Wang L;Nomura Y;Satar G;Gordon D;Gurevitz M;Goldin AL;Dong K
• 通讯作者: Dong K

Bioallethrin activates specific olfactory sensory neurons and elicits spatial repellency in Aedes aegypti.

• DOI: 10.1002/ps.6682
• 发表时间: 2022-03
• 期刊: Pest management science
• 影响因子: 4.1
• 作者: Valbon W;Andreazza F;Oliveira EE;Liu F;Feng B;Hall M;Klimavicz J;Coats JR;Dong K
• 通讯作者: Dong K

Distinct roles of the DmNav and DSC1 channels in the action of DDT and pyrethroids.

• DOI: 10.1016/j.neuro.2015.02.001
• 发表时间: 2015-03
• 期刊: NEUROTOXICOLOGY
• 影响因子: 3.4
• 作者: Rinkevich, Frank D.;Du, Yuzhe;Tolinski, Josh;Ueda, Atsushi;Wu, Chun-Fang;Zhorov, Boris S.;Dong, Ke
• 通讯作者: Dong, Ke

Alanine to valine substitutions in the pore helix IIIP1 and linker-helix IIIL45 confer cockroach sodium channel resistance to DDT and pyrethroids.

• DOI: 10.1016/j.neuro.2016.06.009
• 发表时间: 2017-05
• 期刊: Neurotoxicology
• 影响因子: 3.4
• 作者: Chen M;Du Y;Nomura Y;Zhu G;Zhorov BS;Dong K
• 通讯作者: Dong K