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.
Department of Biochemistry and Molecular Biology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Nat Chem Biol. 2020 Nov;16(11):1246-1254. doi: 10.1038/s41589-020-0627-5. Epub 2020 Aug 17.
The diamide insecticide class is one of the top-selling insecticides globally. They are used to control a wide range of pests by targeting their ryanodine receptors (RyRs). Here, we report the highest-resolution cryo-electron microscopy (cryo-EM) structure of RyR1 in the open state, in complex with the anthranilic diamide chlorantraniliprole (CHL). The 3.2-Å local resolution map facilitates unambiguous assignment of the CHL binding site. The molecule induces a conformational change by affecting the S4-S5 linker, triggering channel opening. The binding site is further corroborated by mutagenesis data, which reveal how diamide insecticides are selective to the Lepidoptera group of insects over honeybee or mammalian RyRs. Our data reveal that several pests have developed resistance via two mechanisms, steric hindrance and loss of contact. Our results provide a foundation for the development of highly selective pesticides aimed at overcoming resistance and therapeutic molecules to treat human myopathies.
二酰胺类杀虫剂是全球最畅销的杀虫剂之一。它们通过作用于肌质网ryanodine 受体（RyRs）来控制广泛的害虫。在这里，我们报告了开放状态下 RyR1 与邻苯二甲酰胺氯虫苯甲酰胺（CHL）复合物的最高分辨率冷冻电镜（cryo-EM）结构。3.2 Å 的局部分辨率图有助于明确 CHL 结合位点的分配。该分子通过影响 S4-S5 连接子来诱导构象变化，从而触发通道打开。突变数据进一步证实了结合位点的存在，该数据揭示了二酰胺类杀虫剂如何对鳞翅目昆虫具有选择性，而对蜜蜂或哺乳动物 RyRs 没有选择性。我们的数据表明，一些害虫已经通过两种机制产生了抗药性，即空间位阻和接触丧失。我们的研究结果为开发旨在克服抗药性的高度选择性杀虫剂和治疗人类肌肉疾病的治疗分子提供了基础。
