The synthesis, structural characterization, and receptor specificity of the α-conotoxin Vc1.1
The synthesis, structural characterization, and receptor specificity of the α-conotoxin Vc1.1
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DOI：
10.1074/jbc.m604550200
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发表时间：
2006-08-11
影响因子：
4.8
通讯作者：
Craik, David J.
中科院分区：
文献类型：
--
作者：
Clark, Richard J.;Fischer, Harald;Craik, David J.
α-芋螺毒素Vc1.1是一种具有二硫键的小分子肽，目前正被开发用于治疗神经性疼痛。本研究描述了Vc1.1的合成、二硫键连接方式的确定以及利用核磁共振波谱法对其三维结构的测定。研究表明，Vc1.1以浓度依赖的方式抑制分离的牛嗜铬细胞中尼古丁诱发的膜电流，并且相较于中枢亚型，它优先作用于外周烟碱型乙酰胆碱受体（nAChR）亚型。具体而言，Vc1.1对含α3的nAChR亚型具有选择性。Vc1.1的三维结构包含一个从Pro(6)到Asp(11)的小α-螺旋，并由在其他α-芋螺毒素中所见的I - III、II - IV二硫键连接方式所支撑。将Vc1.1的结构与其他α-芋螺毒素进行比较，并结合nAChR选择性数据，表明第6位的保守脯氨酸对结合很重要，而该肽C末端部分的一些残基对选择性有贡献。此处报道的结构应为Vc1.1或其类似物作为镇痛药的进一步开发开辟新的机遇。
The alpha-conotoxin Vc1.1 is a small disulfide-bonded peptide currently in development as a treatment for neuropathic pain. This study describes the synthesis, determination of the disulfide connectivity, and the determination of the three-dimensional structure of Vc1.1 using NMR spectroscopy. Vc1.1 was shown to inhibit nicotine-evoked membrane currents in isolated bovine chromaffin cells in a concentration-dependent manner and preferentially targets peripheral nicotinic acetylcholine receptor (nAChR) subtypes over central subtypes. Specifically, Vc1.1 is selective for alpha 3-containing nAChR subtypes. The three-dimensional structure of Vc1.1 comprises a small alpha-helix spanning residues Pro(6) to Asp(11) and is braced by the I-III, II-IV disulfide connectivity seen in other alpha-conotoxins. A comparison of the structure of Vc1.1 with other alpha-conotoxins, taken together with nAChR selectivity data, suggests that the conserved proline at position 6 is important for binding, whereas a number of residues in the C-terminal portion of the peptide contribute toward the selectivity. The structure reported here should open new opportunities for further development of Vc1.1 or analogues as analgesic agents.