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首页> 外文期刊>Biochemistry >NMR solution conformation of an antitoxic analogue of alpha-conotoxin GI: identification of a common nicotinic acetylcholine receptor alpha 1-subunit binding surface for small ligands and alpha-conotoxins.
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NMR solution conformation of an antitoxic analogue of alpha-conotoxin GI: identification of a common nicotinic acetylcholine receptor alpha 1-subunit binding surface for small ligands and alpha-conotoxins.

机译：核糖核酸抗毒素类似物GI的NMR溶液构象：常见的烟碱型乙酰胆碱受体α1-亚基结合表面对小配体和α-毒素的鉴定。

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摘要

The three-dimensional solution conformation of an 11-residue antitoxic analogue of alpha-conotoxin GI, des-Glu1-[Cys3Ala]-des-Cys13-conotoxin GI (CANPACGRHYS-NH(2), designated "GI-15" henceforth), has been determined using two-dimensional (1)H NMR spectroscopy. The disulfide loop region (1C-6C) and the C-terminal tail (8R-11S) are connected by a flexible hinge formed near 7G, and the pairwise backbone rmsds for the former and the latter are 0.58 and 0.65 A, respectively. Superpositioning GI-15 with the structure of alpha-conotoxin GI shows that the two share an essentially identical fold in the common first disulfide loop region (1C-6C). However, the absence of the second disulfide loop in GI-15 results in segmental motion of the C-terminal half, causing the key receptor subtype selectivity residue 8R (Arg9 in alpha-conotoxin GI) to lose its native spatial orientation. The combined features of structural equivalence in the disulfide loop and a mobile C-terminal tail appear to be responsible for the activity of GI-15 as a competitive antagonist against native toxin. Electrostatic surface potential comparisons of the first disulfide region of GI-15 with other alpha-conotoxins or receptor-bound states of acetylcholine and d-tubocurarine show a common protruding surface that may serve as the minimal binding determinant for the neuromuscular acetylcholine receptor alpha 1-subunit. On the basis of the original "Conus toxin macrosite model" [Olivera, B. M., Rivier, J., Scott, J. K., Hillyard, D. R., and Cruz, L. J. (1991) J. Biol. Chem. 266, 1923-1936], we propose a revised binding model which incorporates these results.
机译：11-残基抗毒素类似物des-Glu1- [Cys3Ala] -des-Cys13-conotoxin GI（CANPACGRHYS-NH（2），此后称为“ GI-15”）的三维残基类似物的三维溶液构象，已使用二维（1）H NMR光谱测定。二硫化物环区（1C-6C）和C末端尾部（8R-11S）通过在7G附近形成的柔性铰链连接，前者和后者的成对骨架rmsds分别为0.58和0.65A。具有α-芋螺毒素GI结构的GI-15叠加显示，两者在共同的第一二硫键环区域（1C-6C）中具有基本相同的折叠。但是，GI-15中不存在第二个二硫键环会导致C末端一半发生分段运动，从而导致关键受体亚型选择性残基8R（α-芋螺毒素GI中的Arg9）失去其固有的空间方向。二硫键环和可移动的C末端尾部的结构等效性的组合特征似乎是GI-15活性的竞争者，它是针对天然毒素的竞争性拮抗剂。 GI-15的第一二硫键区域与乙酰胆碱和d-微管尿素的其他α-芋螺毒素或受体结合状态的静电表面电势比较显示，一个共同的凸出表面可作为神经肌肉乙酰胆碱受体α1-的最小结合决定因素亚基。根据原始的“ Conus毒素宏观位点模型” [Olivera，B.M.，Rivier，J.，Scott，J.K.，Hillyard，D.R.和Cruz，L.J.（1991）J.化学266，1923-1936]，我们提出了一种修正的约束模型，其中包含了这些结果。

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