Abstract

The growing resistance of insects to chemical pesticides is reducing the effectiveness of conventional methods for pest control and thus, the development of novel insecticidal agents is imperative. Scorpion toxins specific for insect voltage-gated sodium channels (Na_vs) have been considered as one of the most promising insecticide alternatives due to their host specificity, rapidly evoked toxicity, biodegradability, and the lack of resistance. However, they have not been developed for uses in agriculture and public health, mainly because of a limited understanding of their molecular and evolutionary basis controlling their phylogenetic selectivity. Here, we show that the traditionally defined insect-selective scorpion toxin LqhIT2 specifically captures a prey Na_v through a conserved trapping apparatus comprising a three-residue-formed cavity and a structurally adjacent leucine. The former serves as a detector to recognize and bind a highly exposed channel residue conserved in insects and spiders, two major prey items for scorpions; and the latter subsequently seizes the “moving” voltage sensor via hydrophobic interactions to reduce activation energy for channel opening, demonstrating its action in an enzyme-like manner. Based on the established toxin-channel interaction model in combination with toxicity assay, we enlarged the toxic spectrum of LqhIT2 to spiders and certain other arthropods. Furthermore, we found that genetic background-dependent cavity shapes determine the species selectivity of LqhIT2-related toxins. We expect that the discovery of the trapping apparatus will improve our understanding of the evolution and design principle of Na_v-targeted toxins from a diversity of arthropod predators and accelerate their uses in pest control.

中文翻译：

---

蝎毒素如何选择性地捕获猎物钠通道：分子和进化的基础被发现。

摘要

昆虫对化学农药的抵抗力不断增强，这降低了常规害虫防治方法的有效性，因此，开发新型杀虫剂势在必行。昆虫电压门控性钠离子通道（Na _v s）特有的蝎毒素由于其宿主特异性，快速诱发的毒性，可生物降解性和缺乏抗性而被认为是最有希望的杀虫剂替代品之一。但是，尚未开发出用于农业和公共卫生的药物，这主要是因为对控制其系统选择性的分子和进化基础的了解有限。在这里，我们显示了传统上定义的昆虫选择性蝎毒LqhIT2专门捕获猎物Na _v通过保守的捕获装置，该捕获装置包括三个残基形成的腔和结构上相邻的亮氨酸。前者用作检测器，以识别并结合在昆虫和蜘蛛中保守的高度暴露的通道残留物，而昆虫和蜘蛛是蝎子的两个主要猎物。后者随后通过疏水相互作用抓住“移动”电压传感器，以减少用于通道打开的激活能量，从而以酶样方式证明其作用。基于已建立的毒素通道相互作用模型并结合毒性试验，我们扩大了LqhIT2对蜘蛛和某些其他节肢动物的毒性谱。此外，我们发现遗传背景依赖性腔形状决定了LqhIT2相关毒素的物种选择性。来自多种节肢动物捕食者的_v靶向毒素，并加速其在害虫控制中的使用。