Dutertre Sébastien, Lewis Richard J
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld 4072, Australia.
Biochem Pharmacol. 2006 Sep 14;72(6):661-70. doi: 10.1016/j.bcp.2006.03.027. Epub 2006 Apr 22.
Venomous species have evolved cocktails of bioactive peptides to facilitate prey capture. Given their often exquisite potency and target selectivity, venom peptides provide unique biochemical tools for probing the function of membrane proteins at the molecular level. In the field of the nicotinic acetylcholine receptors (nAChRs), the subtype specific snake alpha-neurotoxins and cone snail alpha-conotoxins have been widely used to probe receptor structure and function in native tissues and recombinant systems. However, only recently has it been possible to generate an accurate molecular view of these nAChR-toxin interactions. Crystal structures of AChBP, a homologue of the nAChR ligand binding domain, have now been solved in complex with alpha-cobratoxin, alpha-conotoxin PnIA and alpha-conotoxin ImI. The orientation of all three toxins in the ACh binding site confirms many of the predictions obtained from mutagenesis and docking simulations on homology models of mammalian nAChR. The precise understanding of the molecular determinants of these complexes is expected to contribute to the development of more selective nAChR modulators. In this commentary, we review the structural data on nAChR-toxin interactions and discuss their implications for the design of novel ligands acting at the nAChR.
有毒物种已经进化出生物活性肽混合物以促进猎物捕获。鉴于毒液肽通常具有极高的效力和靶点选择性，它们为在分子水平上探究膜蛋白的功能提供了独特的生化工具。在烟碱型乙酰胆碱受体（nAChRs）领域，亚型特异性蛇α-神经毒素和芋螺α-芋螺毒素已被广泛用于探究天然组织和重组系统中受体的结构和功能。然而，直到最近才有可能生成这些nAChR-毒素相互作用的精确分子视图。现已解析出与α-眼镜蛇毒素、α-芋螺毒素PnIA和α-芋螺毒素ImI形成复合物的nAChR配体结合域同源物AChBP的晶体结构。所有三种毒素在乙酰胆碱结合位点的取向证实了许多从对哺乳动物nAChR同源模型进行的诱变和对接模拟中获得的预测。对这些复合物分子决定因素的精确理解有望推动更具选择性的nAChR调节剂的开发。在这篇评论中，我们回顾了关于nAChR-毒素相互作用的结构数据，并讨论了它们对设计作用于nAChR的新型配体的意义。
