Characterization of a T-superfamily conotoxin TxVC from Conus textile that selectively targets neuronal nAChR subtypes.
Characterization of a T-superfamily conotoxin TxVC from Conus textile that selectively targets neuronal nAChR subtypes.
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DOI：
10.1016/j.bbrc.2014.10.055
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发表时间：
2014-11
影响因子：
3.1
通讯作者：
Shuo Wang;Tianpeng Du;Zhuguo Liu;Sheng Wang;Ying Wu;Jiuping Ding;Lingfa Jiang;Qiuyun Dai
中科院分区：
文献类型：
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作者：
Shuo Wang;Tianpeng Du;Zhuguo Liu;Sheng Wang;Ying Wu;Jiuping Ding;Lingfa Jiang;Qiuyun Dai
T-超家族芋螺毒素具有典型的“CC-CC”半胱氨酸模式，并且已知主要靶向钙或钠离子通道。近年来，我们对一系列T-超家族芋螺毒素的作用靶点进行了筛选，发现了一种新的T-超家族芋螺毒素TxVC（KPCCSIHDNSCCGL-NH 2）。它选择性靶向神经元烟碱乙酰胆碱受体（nAChR）亚型α4β2和α3β2，IC 50值分别为343.4和1047.2 nM，但对DRG细胞的电压门控钾、钠或钙通道，HEK 293细胞表达的BK通道或LβT2细胞的Kv通道均未表现出明显的药理作用。其Ala突变体抑制活性的变化、NMR结构以及基于其他芋螺毒素靶向nAChR α4β2的分子模拟结果均表明，残基Ile 6和Leu 14是主要的疏水药效基团。据我们所知，这是第一个抑制神经元nAChR并对α4β2具有高结合亲和力的T超家族芋螺毒素。这一发现将扩大知识的T-超家族芋螺毒素的目标和模体信息可以帮助设计新的nAChR抑制剂。
T-superfamily conotoxins have a typical cysteine pattern of “CC–CC”, and are known to mainly target calcium or sodium ion channels. Recently, we screened the targets of a series of T-superfamily conotoxins and found that a new T-superfamily conotoxin TxVC (KPCCSIHDNSCCGL-NH2) from the venom ofConus textile. It selectively targeted the neuronal nicotinic acetylcholine receptor (nAChR) subtypes α4β2 and α3β2, with IC50values of 343.4 and 1047.2 nM, respectively, but did not exhibit obvious pharmacological effects on voltage-gated potassium, sodium or calcium channel in DRG cells, the BK channels expressed in HEK293 cells, or the Kv channels in LβT2 cells. The changes in the inhibitory activities of its Ala mutants, the NMR structure, and molecular simulation results based on other conotoxins targeting nAChR α4β2, all demonstrated that the residues Ile6and Leu14were the main hydrophobic pharmacophores. To our best knowledge, this is the first T-superfamily conotoxin that inhibits neuronal nAChRs and possesses high binding affinity to α4β2. This finding will expand the knowledge of the targets of T-superfamily conotoxins and the motif information could help the design of new nAChR inhibitors.