Differential molecular information of maurotoxin peptide recognizing IK(Ca) and Kv1.2 channels explored by computational simulation.
Differential molecular information of maurotoxin peptide recognizing IK(Ca) and Kv1.2 channels explored by computational simulation.
复制标题
通过计算模拟探索毛乌毒素肽识别IKCa和Kv1.2通道的差异分子信息
DOI：
10.1186/1472-6807-11-3
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发表时间：
2011-01-25
影响因子：
--
通讯作者：
Wang B
中科院分区：
文献类型：
--
作者：
Yi H;Qiu S;Wu Y;Li W;Wang B
背景
蝎毒素是离子通道研究的宝贵工具，也是治疗人类离子通道病的潜在药物。然而，确定毒素肽和离子通道之间多种相互作用的分子基础仍然是一项悬而未决的任务。抑制肽 Maurotoxin (MTX) 以大致相同的效力并使用相同的功能残基识别远缘相关的 IKCa 和 Kv1.2 通道，但它们的差异结合机制仍然难以捉摸。在本研究中，我们应用计算方法探索MTX与Kv1.2和IKCa通道的差异结合模式，这将有助于了解通道-毒素相互作用的多样性并加速基于毒素的药物设计。
结果
通过结合多种计算方法并与之前的MTX-Kv1.2复合物模型进行深入比较，获得了相当稳定的MTX-IKCa复合物。类似地，MTX 采用 β-折叠结构作为结合两个通道的相互作用表面，Lys23 封闭孔。相比之下，MTX 的其他关键残基 Lys27、Lys30 和 Tyr32 在与 IKCa 通道关联时采用不同的相互作用。此外，IKCa通道转塔上的残基Gln229、Ala230、Ala233和Thr234与MTX形成极性和非极性相互作用，而Kv1.2的转塔几乎不参与识别MTX。总之，MTX 和结合复合物的 IKCa 通道上的相互作用残基对表明静电和范德华相互作用对稳定的 MTX-IKCa 复合物的形成同样有贡献，与主要由静电力介导的 MTX-Kv1.2 结合相反。
结论
尽管 IKCa 和 Kv1.2 通道具有相似的药理学特征，但 MTX 在两个关联过程中采用了完全不同的模式。这里公布的所有分子信息不仅可以更好地理解 IKCa 和 Kv1.2 通道之间的结构差异，而且还提供新颖的结构线索，有助于设计更具选择性的分子探针来区分这两个通道。
Background
Scorpion toxins are invaluable tools for ion channel research and are potential drugs for human channelopathies. However, it is still an open task to determine the molecular basis underlying the diverse interactions between toxin peptides and ion channels. The inhibitory peptide Maurotoxin (MTX) recognized the distantly related IKCa and Kv1.2 channel with approximately the same potency and using the same functional residues, their differential binding mechanism remain elusive. In this study, we applied computational methods to explore the differential binding modes of MTX to Kv1.2 and IKCa channels, which would help to understand the diversity of channel-toxin interactions and accelerate the toxin-based drug design.
Results
A reasonably stable MTX-IKCa complex was obtained by combining various computational methods and by in-depth comparison with the previous model of the MTX-Kv1.2 complex. Similarly, MTX adopted the β-sheet structure as the interacting surface for binding both channels, with Lys23 occluding the pore. In contrast, the other critical residues Lys27, Lys30, and Tyr32 of MTX adopted distinct interactions when associating with the IKCa channel. In addition, the residues Gln229, Ala230, Ala233, and Thr234 on the IKCa channel turret formed polar and non-polar interactions with MTX, whereas the turret of Kv1.2 was almost not involved in recognizing MTX. In all, the pairs of interacting residues on MTX and the IKCa channel of the bound complex indicated that electrostatic and Van der Waal interactions contributed equally to the formation of a stable MTX-IKCa complex, in contrast to the MTX-Kv1.2 binding that is dominantly mediated by electrostatic forces.
Conclusions
Despite sharing similar pharmacological profiles toward both IKCa and Kv1.2 channels, MTX adopted totally diverging modes in the two association processes. All the molecular information unveiled here could not only offer a better understanding about the structural differences between the IKCa and Kv1.2 channels, but also provide novel structural clews that will help in the designing of more selective molecular probes to discriminate between these two channels.
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影响因子：
64.8
作者：
Ruta, V;Jiang, YX;MacKinnon, R
通讯作者：
MacKinnon, R
影响因子：
3.6
作者：
Castle, NA;London, DO;Sabatier, JM
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Sabatier, JM
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56.9
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HIDALGO, P;MACKINNON, R
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MACKINNON, R
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作者：
Avdonin, V;Nolan, B;Hoshi, T
通讯作者：
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