Molecular interaction of δ-conopeptide EVIA with voltage-gated Na(+) channels.
Molecular interaction of δ-conopeptide EVIA with voltage-gated Na(+) channels.
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δ-conopeptide EVIA 与电压门控 Na( ) 通道的分子相互作用
DOI：
10.1016/j.bbagen.2016.06.013
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Tietze
中科院分区：
文献类型：
--
作者：
Tietze;Leipold;Heimer;Winschel;Heinemann;Tietze
尽管这些信息对于药物开发及其作为药物先导物的使用是必不可少的，但对于大量的康德肽而言，与结构-活性关系相关的基本知识是不可缺少的。方法采用电生理学和分子模拟相结合的实验与理论相结合的方法，鉴定电压门控Na+通道上con多肽δ-EVIA结合位点，并深入了解毒素的作用方式。结果合成了共肽类化合物δ-EVIA，并通过核磁共振光谱对其结构进行了重新测定，进行了分子对接研究。分子对接和分子动力学模拟研究涉及静息构象中的区域IV电压传感器和部分区域I S5跨膜段。功能研究刺激了分子模型，证明了神经元NaV1.7通道的I和IV结构域对毒素作用的重要性。结论δ- evia与其他电压传感器毒素如锥体毒素δ-SVIE和各种蝎子α-毒素具有相同的结合表位。与以往的硅毒素结合研究相反，我们在此提出了一种电压传感器毒素的硅毒素结合研究，包括由电压传感器静息结构域IV和结构域i的S5组成的整个毒素结合位点。深入分析其与通道靶点的相互作用，可以获得作用模式的信息，也可能有助于揭示电压依赖性通道门控和激活和失活耦合的机制。
BackgroundFor a large number of conopeptides basic knowledge related to structure-activity relationships is unavailable although such information is indispensable with respect to drug development and their use as drug leads.MethodsA combined experimental and theoretical approach employing electrophysiology and molecular modeling was applied for identifying the conopeptide δ-EVIA binding site at voltage-gated Na+channels and to gain insight into the toxin's mode of action.ResultsConopeptide δ-EVIA was synthesized and its structure was re-determined by NMR spectroscopy for molecular docking studies. Molecular docking and molecular dynamics simulation studies were performed involving the domain IV voltage sensor in a resting conformation and part of the domain I S5 transmembrane segment. Molecular modeling was stimulated by functional studies, which demonstrated the importance of domains I and IV of the neuronal NaV1.7 channel for toxin action.Conclusionsδ-EVIA shares its binding epitope with other voltage-sensor toxins, such as the conotoxin δ-SVIE and various scorpion α-toxins. In contrast to previousin silicotoxin binding studies, we present herein silicobinding studies of a voltage-sensor toxin including the entire toxin binding site comprising the resting domain IV voltage sensor and S5 of domain I.General significanceThe prototypical voltage-sensor toxin δ-EVIA is suited for the elucidation of its binding epitope; in-depth analysis of its interaction with the channel target yields information on the mode of action and might also help to unravel the mechanism of voltage-dependent channel gating and coupling of activation and inactivation.
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2,2-二甲基噻唑烷作为锁定顺式脯氨酸酰胺键的案例研究：δ-芋螺毒素 EVIA 肽类似物的合成、NMR 和分子模型研究。
影响因子：
3.2
作者：
S. Chierici;M. Jourdan;Mélanie Figuet;P. Dumy
通讯作者：
P. Dumy
ω-芋螺毒素 GVIA、MVIIA 和 CVID：SAR 和临床潜力
影响因子：
5.4
作者：
C. Schroeder;R. Lewis
通讯作者：
R. Lewis
DOI：
10.1073/pnas.86.24.10161
发表时间：
1989-12-01
影响因子：
11.1
作者：
THOMSEN, WJ;CATTERALL, WA
通讯作者：
CATTERALL, WA
影响因子：
3
作者：
Duan, Y;Wu, C;Kollman, P
通讯作者：
Kollman, P
斑芋螺 δ-芋螺毒素 EVIA 的 NMR 溶液结构，选择性作用于脊椎动物神经元 Na+ 通道*[方框]
影响因子：
4.8
作者：
L. Volpon;H. Lamthanh;J. Barbier;N. Gilles;J. Molgó;A. Ménez;J. Lancelin
通讯作者：
J. Lancelin