Faculty of Education, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
J Agric Food Chem. 2011 Apr 13;59(7):2825-8. doi: 10.1021/jf1019455. Epub 2010 Jul 15.
Neonicotinoid agonists selectively act on the insect nicotinic acetylcholine receptor (nAChR). The molecular basis for this specificity is deciphered by comparisons of two acetylcholine binding proteins (AChBPs) with distinct pharmacological profiles that serve as structural homologues for the nAChR subtypes. Aplysia AChBP has high neonicotinoid sensitivity, whereas Lymnaea AChBP has low neonicotinoid sensitivity, pharmacologies reminiscent of insect and vertebrate nAChR subtypes, respectively. The ligand-receptor interactions for these AChBPs were established by chemical and structural neurobiology approaches. Neonicotinoids and nicotinoids bind in a single conformation with Aplysia AChBP, wherein the electronegative nitro or cyano pharmacophore of the neonicotinoid faces in a reversed orientation relative to the cationic nicotinoid functionality. For Lymnaea AChBP, the neonicotinoids have two binding conformations in this vertebrate receptor model, which are completely inverted relative to each other, whereas nicotinoids are nestled in only one conserved conformation. Therefore, the unique binding conformations of nicotinic agonists determine the selective receptor interactions.
烟碱型激动剂选择性地作用于昆虫烟碱型乙酰胆碱受体（nAChR）。通过比较两种具有不同药理学特征的乙酰胆碱结合蛋白（AChBPs），可以揭示这种特异性的分子基础，这两种 AChBPs 作为 nAChR 亚型的结构同源物。贻贝 AChBP 对新烟碱类化合物具有高敏感性，而田螺 AChBP 对新烟碱类化合物的敏感性较低，其药理学特征分别类似于昆虫和脊椎动物 nAChR 亚型。通过化学和结构神经生物学方法确定了这些 AChBPs 的配体-受体相互作用。新烟碱类化合物和烟碱类化合物与贻贝 AChBP 以单一构象结合，其中新烟碱类化合物的带负电荷的硝基或氰基药效团相对于阳离子烟碱类化合物的功能呈反向取向。对于田螺 AChBP，在这种脊椎动物受体模型中，新烟碱类化合物有两种结合构象，它们彼此完全倒置，而烟碱类化合物仅嵌套在一种保守构象中。因此，烟碱型激动剂的独特结合构象决定了选择性的受体相互作用。
