Docking and homology modeling explain inhibition of the human vesicular glutamate transporters
Docking and homology modeling explain inhibition of the human vesicular glutamate transporters
复制标题
DOI：
10.1110/ps.072944707
复制
发表时间：
2007-09-01
期刊：
影响因子：
8
通讯作者：
Hovmoeller, Sven
中科院分区：
文献类型：
--
作者：
Almqvist, Jonas;Huang, Yafei;Hovmoeller, Sven
作为膜转运蛋白，VGLUT1-3 介导兴奋性神经细胞突触前神经末梢的突触小泡摄取谷氨酸。这一功能对于胞吐作用和谷氨酸作为中枢神经系统主要兴奋性神经递质的作用至关重要。这三种转运蛋白在人类中具有 76% 的氨基酸序列同一性，具有高度同源性，但在大脑中的区域表达不同。尽管人们对它们的三维结构知之甚少，但对这些蛋白质的水病分析预测有 12 个由环连接的跨膜片段，这种拓扑结构与主要促进子超家族中的其他成员相似，VGLUT1-3 已在该家族中进行了系统发育分类。在这项工作中，我们基于同一超家族中的远距离细菌同源物，即来自大肠杆菌的甘油-3-磷酸转运蛋白，提出了人类 VGLUT1 蛋白的三维模型。这种结构模型在水溶剂化的磷脂双层的分子动力学模拟中保持稳定，揭示了面向其孔的氨基酸残基，并且可能影响底物易位。 VGLUT1 底物与该孔的对接定位了两个不同的结合位点，抑制剂也以结合亲和力的总体趋势与这些位点结合，这与之前发表的实验数据一致。
As membrane transporter proteins, VGLUT1-3 mediate the uptake of glutamate into synaptic vesicles at presynaptic nerve terminals of excitatory neural cells. This function is crucial for exocytosis and the role of glutamate as the major excitatory neurotransmitter in the central nervous system. The three transporters, sharing 76% amino acid sequence identity in humans, are highly homologous but differ in regional expression in the brain. Although little is known regarding their three- dimensional structures, hydropathy analysis on these proteins predicts 12 transmembrane segments connected by loops, a topology similar to other members in the major facilitator superfamily, where VGLUT1-3 have been phylogenetically classified. In this work, we present a three- dimensional model for the human VGLUT1 protein based on its distant bacterial homolog in the same superfamily, the glycerol- 3-phosphate transporter from Escherichia coli. This structural model, stable during molecular dynamics simulations in phospholipid bilayers solvated by water, reveals amino acid residues that face its pore and are likely to affect substrate translocation. Docking of VGLUT1 substrates to this pore localizes two different binding sites, to which inhibitors also bind with an overall trend in binding affinity that is in agreement with previously published experimental data.