Fredriksson Robert, Lagerström Malin C, Lundin Lars-Gustav, Schiöth Helgi B
Department of Neuroscience, Biomedical Center, Box 593, 75 124 Uppsala, Sweden.
Mol Pharmacol. 2003 Jun;63(6):1256-72. doi: 10.1124/mol.63.6.1256.
The superfamily of G-protein-coupled receptors (GPCRs) is very diverse in structure and function and its members are among the most pursued targets for drug development. We identified more than 800 human GPCR sequences and simultaneously analyzed 342 unique functional nonolfactory human GPCR sequences with phylogenetic analyses. Our results show, with high bootstrap support, five main families, named glutamate, rhodopsin, adhesion, frizzled/taste2, and secretin, forming the GRAFS classification system. The rhodopsin family is the largest and forms four main groups with 13 sub-branches. Positions of the GPCRs in chromosomal paralogons regions indicate the importance of tetraploidizations or local gene duplication events for their creation. We also searched for "fingerprint" motifs using Hidden Markov Models delineating the putative inter-relationship of the GRAFS families. We show several common structural features indicating that the human GPCRs in the GRAFS families share a common ancestor. This study represents the first overall map of the GPCRs in a single mammalian genome. Our novel approach of analyzing such large and diverse sequence sets may be useful for studies on GPCRs in other genomes and divergent protein families.
G蛋白偶联受体（GPCRs）超家族在结构和功能上具有高度多样性，其成员是药物研发中最受关注的靶点之一。我们鉴定出800多条人类GPCR序列，并同时通过系统发育分析对342条独特的功能性非嗅觉人类GPCR序列进行了分析。我们的结果在高自展支持率下显示，有五个主要家族，即谷氨酸、视紫红质、粘附、卷曲/味觉2和分泌素家族，构成了GRAFS分类系统。视紫红质家族是最大的家族，形成了四个主要组群和13个亚分支。GPCRs在染色体旁系同源区域中的位置表明四倍体化或局部基因复制事件对其产生的重要性。我们还使用隐马尔可夫模型搜索“指纹”基序，以描绘GRAFS家族之间的假定相互关系。我们展示了几个共同的结构特征，表明GRAFS家族中的人类GPCRs拥有共同的祖先。这项研究代表了单个哺乳动物基因组中GPCRs的首张全景图。我们分析如此庞大且多样的序列集的新方法可能对其他基因组和不同蛋白质家族中的GPCRs研究有用。
