孤儿受体GPR52晶体结构揭示配体结合新机制

GPR52受体是一种孤儿G蛋白偶联受体(G protein-coupled receptor,GPCR),在大脑中高度表达,是治疗精神疾病和亨廷顿病的潜在治疗靶点,其内源性配体仍不清楚。由于GPR52与任何已知GPCR结构的相似性很低(<20%),无论是同源建模或是结构解析都存在很大困难。缺乏结构信息在很大程度上阻碍了工具配体和药物的发现。上海科技大学生命科学与技术学院i Human研究所徐菲课题组利用X射线晶体学解析了GPR52的三个高分辨率晶体结构--两个无配体结合的APO结构和GPR52结合激动剂小分子的复合物结构。这些结构揭示了GPR52独特的第二个胞外环、新颖的配体结合侧位口袋和特殊扭转的第五个跨膜α螺旋。突变与细胞功能实验验证了研究人员关于GPR52自激活机制的猜想,并提示第二个胞外环对受体的内在激活作用。这些发现为GPR52配体识别的结构基础提供了前所未有的见解,对寻求GPR52内源性配体即脱孤以及理性设计具有不同药理特性的配体化合物具有重要的指导意义。

Crystal structures of orphan GPR52 reveal a novel ligand-binding pocket

The GPR52 receptor is a Class-A orphan G protein-coupled receptor(GPCR)whose endogenous ligand remains elusive.Highly expressed in the brain,it represents a promising therapeutic target for treating psychiatric disease and Huntington’s disease.However,tool ligand and drug discovery have been largely hampered by lacking of structural information due largely to the low homology(<20%)of GPR52 to any known GPCR structure.Research team led by Dr.Fei Xu at Shanghai Tech University reported three high resolution human GPR52 structures with and without a bound ligand.According to the structures,researchers observed a unique configuration of extracellular loop 2(ECL2)that occupies the orthosteric pocket,a novel side pocket and a special winding mode for transmembrane helix 5(TM5).Mutagenesis and functional assay suggested the self-activation by ECL2.These findings provide unprecedented insights into the structural basis of GPR52 ligand recognition that will be valuable for GPR52 deorphanization and will guide the design of diverse ligands with distinct pharmacological properties.