Hadiatullah Hadiatullah, Zhang Yongliang, Samurkas Arthur, Xie Yunxuan, Sundarraj Rajamanikandan, Zuilhof Han, Qiao Jianjun, Yuchi Zhiguang
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China.
Laboratory of Organic Chemistry, Wageningen University & Research, Wageningen, The Netherlands.
Insect Sci. 2022 Dec;29(6):1522-1551. doi: 10.1111/1744-7917.13032. Epub 2022 May 16.
Ion channels, many expressed in insect neural and muscular systems, have drawn huge attention as primary targets of insecticides. With the recent technical breakthroughs in structural biology, especially in cryo-electron microscopy (cryo-EM), many new high-resolution structures of ion channel targets, apo or in complex with insecticides, have been solved, shedding light on the molecular mechanism of action of the insecticides and resistance mutations. These structures also provide accurate templates for structure-based insecticide screening and rational design. This review summarizes the recent progress in the structural studies of 5 ion channel families: the ryanodine receptor (RyR), the nicotinic acetylcholine receptor (nAChR), the voltage-gated sodium channel (VGSC), the transient receptor potential (TRP) channel, and the ligand-gated chloride channel (LGCC). We address the selectivity of the channel-targeting insecticides by examining the conservation of key coordinating residues revealed by the structures. The possible resistance mechanisms are proposed based on the locations of the identified resistance mutations on the 3D structures of the target channels and their impacts on the binding of insecticides. Finally, we discuss how to develop "green" insecticides with a novel mode of action based on these high-resolution structures to overcome the resistance.
离子通道在昆虫神经和肌肉系统中大量表达，作为杀虫剂的主要作用靶点已引起广泛关注。随着结构生物学领域，尤其是冷冻电子显微镜（cryo-EM）技术的最新突破，许多离子通道靶点的新的高分辨率结构已被解析，这些结构包括离子通道靶点的空载形式或与杀虫剂结合的形式，为揭示杀虫剂的作用分子机制及抗性突变提供了线索。这些结构也为基于结构的杀虫剂筛选和合理设计提供了精确模板。本综述总结了5个离子通道家族结构研究的最新进展：兰尼碱受体（RyR）、烟碱型乙酰胆碱受体（nAChR）、电压门控钠通道（VGSC）、瞬时受体电位（TRP）通道和配体门控氯离子通道（LGCC）。我们通过研究结构揭示的关键配位残基的保守性来探讨靶向通道的杀虫剂的选择性。基于已确定的抗性突变在靶标通道三维结构上的位置及其对杀虫剂结合的影响，提出了可能的抗性机制。最后，我们讨论了如何基于这些高分辨率结构开发具有新型作用模式的“绿色”杀虫剂以克服抗性问题。
