Assessment of Homology Templates and an Anesthetic Binding Site within the γ-Aminobutyric Acid Receptor
Assessment of Homology Templates and an Anesthetic Binding Site within the γ-Aminobutyric Acid Receptor
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DOI：
10.1097/aln.0b013e31829e47e3
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发表时间：
2013-11-01
期刊：
影响因子：
8.8
通讯作者：
Trudell, James R.
中科院分区：
文献类型：
--
作者：
Bertaccini, Edward J.;Yoluk, Ozge;Trudell, James R.
背景：麻醉剂通过调节γ-氨基丁酸受体（GABAaR）介导其部分活性.虽然其分子结构仍不清楚，但通过分子模拟了解其与麻醉剂的相互作用已取得重大进展。方法：鱼雷乙酰胆碱受体（nAChR）的结构、人nAChR的4和2亚基的结构、真核谷氨酸门控氯离子通道（GluCl）的结构和原核pH传感通道，用SAlign和3DMA算法比对来自Gloeulocyanviolaceus和Erwiniachenii的序列。用ClustalW对这些结构和GABAaR的结构进行多序列比对。Modeler和Rosetta算法独立地从GluCl模板创建GABAaR的三维结构。CDocker算法对接到结合口袋的丙泊酚衍生物的同源系列，并计算出与已知的GABAaR增强EC（50）s.结果的相关性的结合亲和力得分：模板的多重结构比对显示了一个明确的共识，除了鱼雷nAChR的麻醉效果相关的残留物的位置。在从GluCl产生的GABAaR模型中，在跨膜段1、2和3内调节麻醉作用的残基聚集在和亚基之间的亚基间界面上。结论：同源模板序列比对结果显示，GABAaR跨膜区存在一个亚基间的麻醉剂结合空腔，提示配体对接分数与实验测定的GABAaR增强效应具有相关性。
Background: Anesthetics mediate portions of their activity via modulation of the -aminobutyric acid receptor (GABAaR). Although its molecular structure remains unknown, significant progress has been made toward understanding its interactions with anesthetics via molecular modeling.Methods: The structure of the torpedo acetylcholine receptor (nAChR), the structures of the 4 and 2 subunits of the human nAChR, the structures of the eukaryotic glutamate-gated chloride channel (GluCl), and the prokaryotic pH-sensing channels, from Gloeobacter violaceus and Erwinia chrysanthemi, were aligned with the SAlign and 3DMA algorithms. A multiple sequence alignment from these structures and those of the GABAaR was performed with ClustalW. The Modeler and Rosetta algorithms independently created three-dimensional constructs of the GABAaR from the GluCl template. The CDocker algorithm docked a congeneric series of propofol derivatives into the binding pocket and scored calculated binding affinities for correlation with known GABAaR potentiation EC(50)s.Results: Multiple structure alignments of templates revealed a clear consensus of residue locations relevant to anesthetic effects except for torpedo nAChR. Within the GABAaR models generated from GluCl, the residues notable for modulating anesthetic action within transmembrane segments 1, 2, and 3 converged on the intersubunit interface between and subunits. Docking scores of a propofol derivative series into this binding site showed strong linear correlation with GABAaR potentiation EC50.Conclusion: Consensus structural alignment based on homologous templates revealed an intersubunit anesthetic binding cavity within the transmembrane domain of the GABAaR, which showed a correlation of ligand docking scores with experimentally measured GABAaR potentiation.