https://scholars.lib.ntu.edu.tw/handle/123456789/162632
標題: | 蜘蛛毒蛋白抑制鉀離子通道活性之分子機制 A possible molecular mechanism of hanatoxin binding-modified gating in voltage-gated K- channels |
作者: | 樓國隆 Lou, Kuo-Long |
公開日期: | 2004 | 出版社: | 臺北市:國立臺灣大學醫學院口腔生物科學研究所 | 起(迄)頁: | 392-395 | 來源出版物: | JOURNAL OF MOLECULAR RECOGNITION 16(6); | 摘要: | Potassium channels are membrane proteins that regulate potassium flux across the cell membrane. They contribute to diverse cell functions from control of membrane potential and excitability of neurons and muscles to regulation of cell volume and osmotic balance. The voltage-gated K- channels (Kv) comprise a large family of tetramers that open and close in response to changes in membrane voltage. Six putative transmembrane segments termed S1–S6 are included in each subunit of the tetramer. Among them, S5 and S6 assemble the central pore domain forming the K- selective ion conduction pathway (MacKinnon and Miller, 1989; MacKinnon and Yellen, 1990; Hartmann et al., 1991; MacKinnon, 1991; Yellen et al., 1991; Yool and Schwarz, 1991; Liman et al., 1992; Heginbotham et al., 1994; Ranganathan et al., 1996; Armstrong and Hille, 1998). The first four transmembrane segments (S1–S4) of voltage-gated K channels do not contribute to the simple pore, and appear to underlie their unique voltage-sensing capabilities (Armstrong and Hille, 1998). S4 is an unusual transmembrane segment that contains a large number of basic residues, which has been suggested by considerable study be strongly involved in sensing changes in membrane voltage (Liman et al., 1991; Papazian et al., 1991; Perozo et al., 1994; Aggarwal and MacKinnon, 1996; Bezanilla et al., 1996; Larsson et al., 1996; Mannuzzu et al., 1996; Seoh et al., 1996; Yang et al., 1996; Yusaf et al., 1996; Smith- Maxwell et al., 1998a, 1998b; Ledwell and Aldrich, 1999). The C-terminal part of S3 segment (S3C) is of particular interest because it has been identified as an important region for interaction with various gating modifier toxins (Rogers et al., 1996; Swartz and MacKinnon, 1997a, 1997b; Li- Smerin and Swartz, 1998, 2000; Winterfield and Swartz,2000). Among them, hanatoxin (HaTx1), a 35-amino acid protein isolated from tarantula venom (Swartz and Mac- Kinnon, 1995), shows an inhibition on drk1 (Kv2.1) by shifting activation to more depolarized voltages (Swartz and MacKinnon, 1997a, 1997b). Investigation on the structural and functional correlation between hanatoxin and voltagegated potassium channels has provided quite useful information in analyzing the roles of S3c in K-channel gating (Takahashi et al., 2000; Li-Smerin and Swartz, 1998, 2000, 2001). Previously we have reported (Huang et al., 2001; Lou et al., 2002; Huang, 2002) a docking simulation study describing the exact binding residues required for HaTx1– drk1 interaction and the derived conformational change resulting from binding. However, while further considering the movement presumably towards S4 upon conformational change (Huang et al., 2001), together with the specific binding pocket close to the external crevice depicted from the detailed residue analysis (Lou et al., 2002), we noticed that the structural roles of S3C–S4 proximity in interfering with S4 translocation must be clarified, especially in terms of the length of S3–S4 linker (Mathur et al., 1997; Swartz and MacKinnon, 1997a, 1997b; Gonzalez et al., 2000). In this study, thereby, we extensively and comprehensively compare the docking simulation results of drk1 S3C–HaTx1 to the substitution with shaker S3C sequence. The mutual influence of the proximity of S3C–S4N region is thus discussed. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/22668 | 其他識別: | 922311B002101 | 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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