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: 10397536
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10397536
• 关键词: Agonist; Applications Grants; Arthropod Vectors; Arthropods; Basic Science; Batrachotoxins; Binding Sites; Chemicals; Collaborations; Complex; Computer Models; Cryoelectron Microscopy; Crystallization; 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; Steroids; 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; 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.

项目概要 电压门控钠通道 (Navs) 是多种天然神经毒素和杀虫剂的目标，包括 拟除虫菊酯和钠通道阻滞剂（SCBI）是目前最常用的杀虫剂之一。 对抗传播人类疾病的蚊子和其他节肢动物媒介的重要而有效的武器库。 SCBI 属于新型选择性杀虫剂，有效控制病媒的一个主要挑战是全球性的。 杀虫剂抗性的出现尤其是 Nav 基因的突变导致了抗药性的主要形式。 被称为击倒抗性（kdr），在缺乏真核 Navs 复合物的 3-D 结构的情况下。 拟除虫菊酯或 SCBI，在理解它们的相互作用方面仍然存在重大不确定性（包括其性质） 各自的受体位点）和 kdr 机制在这项拨款提案中，我们利用了最近的优势。 共同 PI 实验室在确定几种真核生物 Nav 的冷冻电镜结构方面取得了突破。 这些导航结构的可用性现在保证了对导航的理解达到前所未有的新水平 我们建议确定 Navs 的冷冻电镜结构。 与拟除虫菊酯、SCBI 和其他三种神经毒素形成复合物，并使用这些结构作为指导进行 全面的系列突变、电生理学和计算模型分析 该更新提案的两个具体目标是：1）确定 Nav-配体相互作用。 真核生物 Nav 与各种拟除虫菊酯复合物，以深入了解拟除虫菊酯的原子机制 和 kdr，以及 2) 研究 Nav 与 SCBI（DCJW 和氰氟胺腙）、类固醇的相互作用机制 激动剂（BTX 和藜芦定）和烷基酰胺杀虫剂 BTG 502。这项研究的结果将推动我们的研究 对拟除虫菊酯、SCBI 和其他神经毒素的分子作用的了解达到了新的水平，从而 促进全球范围内杀虫剂抗药性精确监测和管理的发展， 发现新的安全的导航化学物质，以应对节肢动物疾病传播的全球威胁 向量。