Shiau Yu-Shuan, Huang Po-Tsang, Liou Horng-Huei, Liaw Yen-Chywan, Shiau Yuh-Yuan, Lou Kuo-Long
Institute of Entomology, National Taiwan University, Taipei, Republic of China.
Chem Res Toxicol. 2003 Oct;16(10):1217-25. doi: 10.1021/tx0341097.
Voltage-dependent potassium channel Kv2.1 is widely expressed in mammalian neurons and was suggested responsible for mediating the delayed rectifier (I(K)) currents. Further investigation of the central role of this channel requires the development of specific pharmacology, for instance, the utilization of spider venom toxins. Most of these toxins belong to the same structural family with a short peptide reticulated by disulfide bridges and share a similar mode of action. Hanatoxin 1 (HaTx1) from a Chilean tarantula was one of the earliest discussed tools regarding this and has been intensively applied to characterize the channel blocking not through the pore domain. Recently, more related novel toxins from African tarantulas such as heteroscordratoxins (HmTx) and stromatoxin 1 (ScTx1) were isolated and shown to act as gating modifiers such as HaTx on Kv2.1 channels with electrophysiological recordings. However, further interaction details are unavailable due to the lack of high-resolution structures of voltage-sensing domains in such mammalian Kv channels. Therefore, in the present study, we explored structural observation via molecular docking simulation between toxins and Kv2.1 channels based upon the solution structures of HaTx1 and a theoretical basis of an individual S3(C) helical channel fragment in combination with homology modeling for other novel toxins. Our results provide precise chemical details for the interactions between these tarantula toxins and channel, reasonably correlating the previously reported pharmacological properties to the three-dimensional structural interpretation. In addition, it is suggested that certain subtle structural variations on the interaction surface of toxins may discriminate between the related toxins with different affinities for Kv channels. Evolutionary links between spider peptide toxins and a "voltage sensor paddles" mechanism most recently found in the crystal structure of an archaebacterial K(+) channel, KvAP, are also delineated in this paper.
电压依赖性钾通道Kv2.1在哺乳动物神经元中广泛表达，被认为负责介导延迟整流器（I(K)）电流。对该通道核心作用的进一步研究需要开发特定的药理学方法，例如利用蜘蛛毒液毒素。这些毒素大多属于同一结构家族，由二硫键连接的短肽构成，作用方式相似。来自智利狼蛛的汉毒素1（HaTx1）是最早讨论的相关工具之一，并已被广泛应用于表征非通过孔道结构域的通道阻断作用。最近，从非洲狼蛛中分离出了更多相关的新型毒素，如异蝎毒素（HmTx）和基质毒素1（ScTx1），通过电生理记录表明它们在Kv2.1通道上与HaTx一样可作为门控修饰剂。然而，由于此类哺乳动物Kv通道电压感应结构域缺乏高分辨率结构，进一步的相互作用细节尚不清楚。因此，在本研究中，我们基于HaTx1的溶液结构以及单个S3(C)螺旋通道片段的理论基础，并结合其他新型毒素的同源建模，通过毒素与Kv2.1通道之间的分子对接模拟来探索结构观察。我们的结果提供了这些狼蛛毒素与通道之间相互作用的精确化学细节，合理地将先前报道的药理学特性与三维结构解释相关联。此外，研究表明毒素相互作用表面的某些细微结构变化可能区分对Kv通道具有不同亲和力的相关毒素。本文还阐述了蜘蛛肽毒素与古细菌钾通道KvAP晶体结构中最近发现的“电压传感器桨”机制之间的进化联系。
