A model of the nicotinic receptor extracellular domain based on sequence identity and residue location.
A model of the nicotinic receptor extracellular domain based on sequence identity and residue location.
复制标题
基于序列同一性和残基位置的烟碱受体胞外结构域模型。
DOI：
10.1016/s0006-3495(97)78047-0
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
Taylor,P
中科院分区：
文献类型：
--
作者：
Tsigelny,I;Sugiyama,N;Sine,SM;Taylor,P
我们利用与已知晶体结构的铜结合蛋白、质体青素和伪azurin的序列同源性，以及最近的位点特异性诱变、抗体定位和位点定向标记研究的数据，对烟碱乙酰胆碱受体中单个亚基（氨基酸31-200）的胞外结构域进行了建模。这些数据形成了一个初始模型，并通过分子动力学和力学以及静电和溶剂化能计算进行了改进。α 1亚基的31 ~ 164残基与同源受体亚基的相应残基序列与模板蛋白中以多个发夹环为特征的质体青素和伪蓝蛋白阳离子结合位点的核心序列相似。除了更详细地定义包含激动剂和竞争拮抗剂结合位点的亚基界面外，研究结果还表明，带负电荷的残基聚集在旨在减少复合物静电自由能的结构域中。静电因子似乎也能将配体结合界面α γ和α δ与五聚体受体上的其他三个界面区分开来。
We have modeled the extracellular domains of individual subunits (amino acids 31–200) in the nicotinic acetylcholine receptor using sequence homology with copper binding proteins of known crystal structure, plastocyanin and pseudoazurin, and data from recent site-specific mutagenesis, antibody mapping, and site-directed labelling studies. These data formed an initial model that was refined using molecular dynamics and mechanics as well as electrostatic and solvation energy calculations. The sequences between residues 31 and 164 in the alpha 1-subunit and corresponding residues in homologous receptor subunits show similarity with the core sequence of the cation binding site in plastocyanin and pseudoazurin, a region in the template proteins characterized by multiple hairpin loops. In addition to defining the subunit interfaces that comprise the site for agonist and competitive antagonist binding in more detail, the findings show that negatively charged residues cluster in domains arranged to diminish electrostatic free energy of the complex. Electrostatic factors also appear to distinguish the ligand binding interfaces, alpha gamma and alpha delta, from the other three interfaces on the pentameric receptor.