Development of a μO-Conotoxin Analogue with Improved Lipid Membrane Interactions and Potency for the Analgesic Sodium Channel NaV1.8
Development of a μO-Conotoxin Analogue with Improved Lipid Membrane Interactions and Potency for the Analgesic Sodium Channel NaV1.8
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DOI：
10.1074/jbc.m116.721662
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发表时间：
2016-05-27
影响因子：
4.8
通讯作者：
Vetter, Irina
中科院分区：
文献类型：
--
作者：
Deuis, Jennifer R.;Dekan, Zoltan;Vetter, Irina
魔芋螺毒素mrVIA、mrVIB和mfVIA抑制电压门控钠通道Na(V)1.8，这是一个很好的治疗疼痛的靶点；然而，人们对定义这一活性的残基或结构元件知之甚少。在这项研究中，我们确定了MfVIA的三维结构，检测了它的膜结合特性，进行了丙氨酸扫描突变，并在人Na(V)1.8处确定了对其活性重要的残基。第二轮突变导致了(E5K，E8K)MfVIA，与MfVIA相比，MfVIA具有更大的表面正电荷和更强的脂膜亲和力。在小鼠福尔马林实验中，该类似物在Na(V)1.8时有较强的镇痛作用。
The mu O-conotoxins MrVIA, MrVIB, and MfVIA inhibit the voltage-gated sodium channel Na(V)1.8, a well described target for the treatment of pain; however, little is known about the residues or structural elements that define this activity. In this study, we determined the three-dimensional structure of MfVIA, examined its membrane binding properties, performed alanine-scanning mutagenesis, and identified residues important for its activity at human Na(V)1.8. Asecond round of mutations resulted in (E5K,E8K)MfVIA, a double mutant with greater positive surface charge and greater affinity for lipid membranes compared with MfVIA. This analogue had increased potency at Na(V)1.8 and was analgesic in the mouse formalin assay.