Structural Basis of Binding and Inhibition of Novel Tarantula Toxins in Mammalian Voltage-Dependent Potassium Channels

详细信息    查看全文

• 作者：Yu-Shuan Shiau ; Po-Tsang Huang ; Horng-Huei Liou ; Yen-Chywan Liaw ; Yuh-Yuan Shiau ; and Kuo-Long Lou
• 刊名：Chemical Research in Toxicology
• 出版年：2003
• 出版时间：October 2003
• 年：2003
• 卷：16
• 期：10
• 页码：1217 - 1225
• 全文大小：717K
• 年卷期：v.16,no.10(October 2003)
• ISSN：1520-5010

文摘

Voltage-dependent potassium channel Kv2.1 is widely expressed in mammalian neuronsand was suggested responsible for mediating the delayed rectifier (I_K) currents. Furtherinvestigation 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 thesame structural family with a short peptide reticulated by disulfide bridges and share a similarmode of action. Hanatoxin 1 (HaTx1) from a Chilean tarantula was one of the earliest discussedtools regarding this and has been intensively applied to characterize the channel blocking notthrough the pore domain. Recently, more related novel toxins from African tarantulas such asheteroscordratoxins (HmTx) and stromatoxin 1 (ScTx1) were isolated and shown to act as gatingmodifiers such as HaTx on Kv2.1 channels with electrophysiological recordings. However,further interaction details are unavailable due to the lack of high-resolution structures ofvoltage-sensing domains in such mammalian Kv channels. Therefore, in the present study,we explored structural observation via molecular docking simulation between toxins and Kv2.1channels based upon the solution structures of HaTx1 and a theoretical basis of an individualS3_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 toxinsand channel, reasonably correlating the previously reported pharmacological properties to thethree-dimensional structural interpretation. In addition, it is suggested that certain subtlestructural variations on the interaction surface of toxins may discriminate between the relatedtoxins with different affinities for Kv channels. Evolutionary links between spider peptide toxinsand a "voltage sensor paddles" mechanism most recently found in the crystal structure of anarchaebacterial K⁺ channel, KvAP, are also delineated in this paper.