A novel inhibitor of α9α10 nicotinic acetylcholine receptors from Conus vexillum delineates a new conotoxin superfamily.
A novel inhibitor of α9α10 nicotinic acetylcholine receptors from Conus vexillum delineates a new conotoxin superfamily.
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DOI：
10.1371/journal.pone.0054648
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
McIntosh JM
中科院分区：
文献类型：
--
作者：
Luo S;Christensen S;Zhangsun D;Wu Y;Hu Y;Zhu X;Chhabra S;Norton RS;McIntosh JM
芋螺毒素（CTx）选择性地靶向一系列离子通道和受体，使它们成为探测神经系统功能的广泛使用的工具。芋螺毒素先前已根据信号序列分为超家族，并根据其半胱氨酸框架和生物靶标分为家族。本文报道了一种新的芋螺毒素α B-芋螺毒素XXIVA的克隆和鉴定。该肽不属于任何先前描述的芋螺毒素超家族，并且其Cys残基的排列在芋螺肽中是独特的。此外，与先前表征的芋螺肽毒素（其最初表达为具有信号序列、“pro "区域和毒素编码区域的前原肽前体）相反，α B-XXIVA的前体序列缺乏”pro"区域。预测的40个残基的成熟肽，其中包含四个半胱氨酸，在三个可能的二硫键排列的每一个合成。α B-XXIVA的作用机制研究表明，该肽是一种烟碱乙酰胆碱受体（nAChR）拮抗剂，对α9α10亚型具有最大效力。1H核磁共振（NMR）谱表明，三种α B-XXIVA异构体在水溶液中的结构都很差。这与圆二色性（CD）结果一致，圆二色性结果表明，肽在缓冲液中是非结构化的，但在三氟乙醇（TFE）水溶液中采用部分螺旋构象。α9α10 nAChR是镇痛药和癌症化疗药物开发的重要靶点，α B-nAChXXIVA是一种新的配体，可用于探测该蛋白的结构和功能。
Conotoxins (CTxs) selectively target a range of ion channels and receptors, making them widely used tools for probing nervous system function. Conotoxins have been previously grouped into superfamilies according to signal sequence and into families based on their cysteine framework and biological target. Here we describe the cloning and characterization of a new conotoxin, from Conus vexillum, named αB-conotoxin VxXXIVA. The peptide does not belong to any previously described conotoxin superfamily and its arrangement of Cys residues is unique among conopeptides. Moreover, in contrast to previously characterized conopeptide toxins, which are expressed initially as prepropeptide precursors with a signal sequence, a ‘‘pro’’ region, and the toxin-encoding region, the precursor sequence of αB-VxXXIVA lacks a ‘‘pro’’ region. The predicted 40-residue mature peptide, which contains four Cys, was synthesized in each of the three possible disulfide arrangements. Investigation of the mechanism of action of αB-VxXXIVA revealed that the peptide is a nicotinic acetylcholine receptor (nAChR) antagonist with greatest potency against the α9α10 subtype. 1H nuclear magnetic resonance (NMR) spectra indicated that all three αB-VxXXIVA isomers were poorly structured in aqueous solution. This was consistent with circular dichroism (CD) results which showed that the peptides were unstructured in buffer, but adopted partially helical conformations in aqueous trifluoroethanol (TFE) solution. The α9α10 nAChR is an important target for the development of analgesics and cancer chemotherapeutics, and αB-VxXXIVA represents a novel ligand with which to probe the structure and function of this protein.
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影响因子：
6.1
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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