Prediction of the odorant binding site of olfactory receptor proteins by human-mouse comparisons
Prediction of the odorant binding site of olfactory receptor proteins by human-mouse comparisons
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DOI：
10.1110/ps.03296404
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发表时间：
2004-01-01
期刊：
影响因子：
8
通讯作者：
Lancet, D
中科院分区：
文献类型：
--
作者：
Man, O;Gilad, Y;Lancet, D
嗅觉受体（ORs）是一个大家族的蛋白质参与识别和辨别许多气味。这些受体属于G蛋白偶联受体（GPCR）超家族，其结构数据很少。在这项研究中，我们预测OR蛋白的结合位点残基通过分析一组1441 OR蛋白序列从小鼠和人类。利用的中心观点是，功能性接触残基将在邻位受体对之间保守，但在旁系同源对之间保守性大大降低。使用明智地选择的子集218直系同源物对和518旁系同源物对，我们已经确定了22个序列的位置，都是高度保守的推定的直系同源物和旁系同源物之间的变量。这些残基位于跨膜螺旋2 - 7和受体的第二胞外环上。引人注目的是，尽管预测没有假设结合位点的位置，但这些氨基酸位置聚集在OR结构同源性模型中的口袋周围，主要面向内腔。我们建议，确定的位置构成的气味结合位点。这一结论得到以下观察结果的支持：除了一个以外，所有预测的结合位点残基都对应于其他视紫红质样GPCR中的配体接触位置。
Olfactory receptors (ORs) are a large family of proteins involved in the recognition and discrimination of numerous odorants. These receptors belong to the G-protein coupled receptor (GPCR) hyperfamily, for which little structural data are available. In this study we predict the binding site residues of OR proteins by analyzing a set of 1441 OR protein sequences from mouse and human. The central insight utilized is that functional contact residues would be conserved among pairs of orthologous receptors, but considerably less conserved among paralogous pairs. Using judiciously selected subsets of 218 ortholog pairs and 518 paralog pairs, we have identified 22 sequence positions that are both highly conserved among the putative orthologs and variable among paralogs. These residues are disposed on transmembrane helices 2 to 7, and on the second extracellular loop of the receptor. Strikingly, although the prediction makes no assumption about the location of the binding site, these amino acid positions are clustered around a pocket in a structural homology model of ORs, mostly facing the inner lumen. We propose that the identified positions constitute the odorant binding site. This conclusion is supported by the observation that all but one of the predicted binding site residues correspond to ligand-contact positions in other rhodopsin-like GPCRs.