Novel conotoxins from Conus striatus and Conus kinoshitai selectively block TTX-resistant sodium channels
Novel conotoxins from Conus striatus and Conus kinoshitai selectively block TTX-resistant sodium channels
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DOI：
10.1021/bi0473408
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发表时间：
2005-05-17
期刊：
影响因子：
2.9
通讯作者：
Olivera, BM
中科院分区：
文献类型：
--
作者：
Bulaj, G;West, PJ;Olivera, BM
众所周知，从捕食性海洋芋螺毒液中分离的肽（“芋螺毒素”）是电压门控离子通道和受体的高效和选择性药理学试剂。我们报告发现两种新的TTX耐钠通道阻滞剂，μ-芋螺毒素SIIIA和KIIIA，从两种锥螺。结合分子生物学技术和化学合成方法对这两种毒素进行了鉴定和表征。这两种肽抑制蛙交感神经节和背根神经节神经元中的TTX抗性钠电流，但对蛙骨骼肌中由TTX敏感性钠通道介导的动作电位的阻断作用较差。在C-末端区域的两种肽和先前表征的μ-芋螺毒素SmIIIA（其也阻断TTX抗性通道）的氨基酸序列是相似的，但是三种肽在它们的第一N-末端环的长度上不同。我们使用分子动力学模拟来分析改变第一环中的残基数量如何影响μ-芋螺毒素的整体结构。我们的研究结果表明，自然发生的截断不影响C-末端环的构象。两者合计，μ-芋螺毒素SmIIIA，SIIIA和KIIIA之间的结构和功能差异提供了一个独特的见解芋螺毒素活性的“进化工程”。
The peptides isolated from venoms of predatory marine Conus snails ("conotoxins") are well-known to be highly potent and selective pharmacological agents for voltage-gated ion channels and receptors. We report the discovery of two novel TTX-resistant sodium channel blockers, mu-conotoxins SIIIA and KIIIA, from two species of cone snails. The two toxins were identified and characterized by combining molecular techniques and chemical synthesis. Both peptides inhibit TTX-resistant sodium currents in neurons of frog sympathetic and dorsal root ganglia but poorly block action potentials in frog skeletal muscle, which are mediated by TTX-sensitive sodium channels. The amino acid sequences in the C-terminal region of the two peptides and of the previously characterized mu-conotoxin SmIIIA (which also blocks TTX-resistant channels) are similar, but the three peptides differ in the length of their first N-terminal loop. We used molecular dynamics simulations to analyze how altering the number of residues in the first loop affects the overall structure of mu-conotoxins. Our results suggest that the naturally occurring truncations do not affect the conformation of the C-terminal loops. Taken together, structural and functional differences among mu-conotoxins SmIIIA, SIIIA, and KIIIA offer a unique insight into the "evolutionary engineering" of conotoxin activity.