https://scholars.lib.ntu.edu.tw/handle/123456789/162629
標題: | 腺核甘三磷酸感受性鉀離子通道膜內區域之表現,純化,及結晶 Structural Basis of Binding and Inhibition of Novel Tarantula Toxins in Mammalian Voltage-Dependent Potassium Channels |
作者: | 樓國隆 Lou, Kuo-Long |
公開日期: | 2003 | 出版社: | 臺北市:國立臺灣大學醫學院口腔生物科學研究所 | 摘要: | Voltage-dependent potassium channel Kv2.1 is widely expressed in mammalian neurons and was suggested responsible for mediating the delayed rectifier (IK) 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 like heteroscordratoxins (HmTx) and stromatoxin 1 (ScTx1) were isolated and shown to act as gating modifiers like 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 S3C 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 3-D 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. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/22665 | 其他識別: | 912311B002046 | Rights: | 國立臺灣大學醫學院口腔生物科學研究所 |
顯示於: | 口腔生物科學研究所 |
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