Lesovoy Dmitry M, Bocharov Eduard V, Lyukmanova Ekaterina N, Kosinsky Yurij A, Shulepko Mikhail A, Dolgikh Dmitry A, Kirpichnikov Mikhail P, Efremov Roman G, Arseniev Alexander S
Division of Structural Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia.
Biophys J. 2009 Oct 7;97(7):2089-97. doi: 10.1016/j.bpj.2009.07.037.
The action of three-finger snake alpha-neurotoxins at their targets, nicotinic acetylcholine receptors (nAChR), is widely studied because of its biological and pharmacological relevance. Most such studies deal only with ligands and receptor models; however, for many ligand/receptor systems the membrane environment may affect ligand binding. In this work we focused on binding of short-chain alpha-neurotoxin II (NTII) from Naja oxiana to the native-like lipid bilayer, and the possible role played by the membrane in delivering the toxin to nAChR. Experimental (NMR and mutagenesis) and molecular modeling (molecular-dynamics simulation) studies revealed a specific interaction of the toxin molecule with the phosphatidylserine headgroup of lipids, resulting in the proper topology of NTII on lipid bilayers favoring the attack of nAChR. Analysis of short-chain alpha-neurotoxins showed that most of them possess a high positive charge and sequence homology in the lipid-binding motif of NTII, implying that interaction with the membrane surrounding nAChR may be common for the toxin family.
由于具有生物学和药理学相关性，三指蛇α-神经毒素作用于其靶点——烟碱型乙酰胆碱受体（nAChR），这一作用得到了广泛研究。大多数此类研究仅涉及配体和受体模型；然而，对于许多配体/受体系统而言，膜环境可能会影响配体结合。在这项研究中，我们聚焦于来自中亚眼镜蛇的短链α-神经毒素II（NTII）与类天然脂质双层的结合，以及膜在将毒素递送至nAChR过程中可能发挥的作用。实验（核磁共振和诱变）和分子建模（分子动力学模拟）研究揭示了毒素分子与脂质的磷脂酰丝氨酸头部基团之间的特异性相互作用，这使得NTII在脂质双层上具有合适的拓扑结构，有利于对nAChR的攻击。对短链α-神经毒素的分析表明，它们中的大多数在NTII的脂质结合基序中具有高正电荷和序列同源性，这意味着与nAChR周围膜的相互作用可能是该毒素家族的共性。
