Neonicotinoid insecticides, which act on nicotinic acetylcholine receptors (nAChRs) in a variety of ways, have extremely low mammalian toxicity, yet the molecular basis of such actions is poorly understood. To elucidate the molecular basis for nAChR-neonicotinoid interactions, a surrogate protein, acetylcholine binding protein from Lymnaea stagnalis (Ls-AChBP) was crystallized in complex with neonicotinoid insecticides imidacloprid (IMI) or clothianidin (CTD). The crystal structures suggested that the guanidine moiety of IMI and CTD stacks with Tyr185, while the nitro group of IMI but not of CTD makes a hydrogen bond with Gln55. IMI showed higher binding affinity for Ls-AChBP than that of CTD, consistent with weaker CH-pi interactions in the Ls-AChBP-CTD complex than in the Ls-AChBP-IMI complex and the lack of the nitro group-Gln55 hydrogen bond in CTD. Yet, the NH at position 1 of CTD makes a hydrogen bond with the backbone carbonyl of Trp143, offering an explanation for the diverse actions of neonicotinoids on nAChRs.

中文翻译：

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Lymnaea stagnalis AChBP 与新烟碱类杀虫剂吡虫啉和噻虫胺复合的晶体结构。

新烟碱类杀虫剂以多种方式作用于烟碱型乙酰胆碱受体 (nAChR)，对哺乳动物的毒性极低，但对此类作用的分子基础知之甚少。为了阐明 nAChR-新烟碱相互作用的分子基础，一种替代蛋白，来自 Lymnaea stagnalis (Ls-AChBP) 的乙酰胆碱结合蛋白与新烟碱类杀虫剂吡虫啉 (IMI) 或噻虫胺 (CTD) 形成复合物结晶。晶体结构表明IMI和CTD的胍部分与Tyr185叠加，而IMI的硝基而非CTD的硝基与Gln55形成氢键。IMI 对 Ls-AChBP 的结合亲和力高于 CTD，与 Ls-AChBP-CTD 复合物中比 Ls-AChBP-IMI 复合物中更弱的 CH-pi 相互作用以及 CTD 中缺乏硝基-Gln55 氢键一致。然而，CTD 1 位的 NH 与 Trp143 的骨架羰基形成氢键，为新烟碱类对 nAChR 的多种作用提供了解释。