Automatic modeling of mammalian olfactory receptors and docking of odorants
Automatic modeling of mammalian olfactory receptors and docking of odorants
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DOI：
10.1093/protein/gzs037
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发表时间：
2012-08-01
影响因子：
2.4
通讯作者：
Sanz, Guenhael
中科院分区：
文献类型：
--
作者：
Launay, Guillaume;Teletchea, Stephane;Sanz, Guenhael
我们提出了一个程序，（i）自动化的同源性建模的哺乳动物嗅觉受体（OR）的基础上的6个三维（3D）结构的G蛋白偶联受体（GPCR）到目前为止，和（ii）执行对接的气味对这些模型，使用的概念，殖民地能量评分的复合物。OR表现出与其他GPCR的低序列相似性，并且目前的比对方法通常不能提供可靠的比对。在这里，我们使用一个折叠识别技术，以获得一个强大的初始对齐。然后，我们将我们的程序应用于我们以前功能特征的人类OR。分析所得到的在silico复合物，支持受体诱变和功能测定在异源表达系统中，表明拮抗剂对接在结合口袋的上部，而激动剂对接在狭窄的下部。我们认为激动剂激活受体的效力取决于它们与结合口袋底部建立紧密相互作用的能力。我们开发了一个网站，允许用户上传GPCR序列，在库中选择配体并获得游离受体和配体受体复合物的3D结构（）。
We present a procedure that (i) automates the homology modeling of mammalian olfactory receptors (ORs) based on the six three-dimensional (3D) structures of G protein-coupled receptors (GPCRs) available so far and (ii) performs the docking of odorants on these models, using the concept of colony energy to score the complexes. ORs exhibit low-sequence similarities with other GPCR and current alignment methods often fail to provide a reliable alignment. Here, we use a fold recognition technique to obtain a robust initial alignment. We then apply our procedure to a human OR that we have previously functionally characterized. The analysis of the resulting in silico complexes, supported by receptor mutagenesis and functional assays in a heterologous expression system, suggests that antagonists dock in the upper part of the binding pocket whereas agonists dock in the narrow lower part. We propose that the potency of agonists in activating receptors depends on their ability to establish tight interactions with the floor of the binding pocket. We developed a web site that allows the user to upload a GPCR sequence, choose a ligand in a library and obtain the 3D structure of the free receptor and ligandreceptor complex ().