Molecular Information of Charybdotoxin Blockade in the Large Conductance Calcium-activated Potassium Channel
Molecular Information of Charybdotoxin Blockade in the Large Conductance Calcium-activated Potassium Channel
复制标题
大电导钙激活钾通道中 Charybdotoxin 阻断的分子信息。
DOI：
10.1021/ci900025n
复制
发表时间：
2009-07-01
影响因子：
5.6
通讯作者：
Li, Wenxin
中科院分区：
文献类型：
--
作者：
Qiu, Su;Yi, Hong;Li, Wenxin
蝎毒素Charybdotoxin（ChTX）是第一个被发现的大电导钙离子和电压依赖性钾离子通道（BK）的肽类抑制剂，但ChTX与BK通道相互作用的化学信息至今仍不清楚。采用组合计算方法，我们得到了一个ChTX-BK复合物的结构模型，它与诱变数据相关性良好。在该复合物中，ChTX主要使用其β折叠结构域将BK通道与保守的孔阻断Lys 27相关联。ChTX的另一个关键的Tyr 36残基位于BK通道的选择性过滤器和S6螺旋连接环上，与BK通道的Gly 291形成氢键。此外，BK通道的独特的转塔区域远离ChTX，这可以解释许多BK通道阻断剂对Kv通道的选择性较低的事实。所有这些信息有助于揭示蝎毒素与钾通道之间的多样性相互作用，并有助于促进特异性抑制剂的分子工程设计。
The scorpion toxin, charybdotoxin (ChTX), is the first identified peptide inhibitor for the large-conductance Ca2+ and voltage-dependent K+ (BK) channel, and the chemical information of the interaction between ChTX and BK channel remains unclear today. Using combined computational methods, we obtained a ChTX-BK complex structure model, which correlated well with the mutagenesis data. In this complex, ChTX mainly used its beta-sheet domains to associate the BK channel with a conserved pore-blocking Lys27. Another crucial Tyr36 residue of ChTX lied over the loop connecting selectivity filter and S6 helix of BK channel, forming a hydrogen bond with Gly291 of BK channel. Besides, the unique turret region of BK channel was found to be far away from bound ChTX, which could explain the fact that many BK channel blockers show less selectivity over Kv channels, Together, all these information is helpful to reveal the diverse interactions between scorpion toxins and potassium channels and can accelerate the molecular engineering of specific inhibitor design.