Allosteric coupling between G-protein binding and extracellular ligand binding sites in GPR52 revealed by (19)F-NMR and cryo-electron microscopy.
Allosteric coupling between G-protein binding and extracellular ligand binding sites in GPR52 revealed by (19)F-NMR and cryo-electron microscopy.
复制标题
作者：
亲爱的编辑，GPR 52是A类孤儿GPCR，已被报道为治疗亨廷顿病、认知障碍、精神分裂症和神经肌肉疾病的靶点。先前的结构测定表明，GPR 52在不存在任何配体的情况下与G蛋白结合时采用活性构象。1提出了一种自激活模型，归因于嵌入在正构配体结合口袋附近的胞外环2（ECL 2）中的内置激动剂基序;这也可以解释GPR 52的高基础活性。合成配体c17与GPR 52侧袋结合，如共晶结构所示。最近，一些与c17具有相似化学结构的新分子已经进入了GPR 52相关疾病的临床前试验。2GPCR的结构和构象动力学研究对于筛选新的配体和理解以前未开发的药物靶点的分子机制至关重要。在这里，我们展示了一个新的冷冻电子显微镜（cryo-EM）结构的GPR 52结合c17在细胞外侧和G蛋白在细胞内侧。通过观察c17中的三氟甲基（图1A）对复合物进行的19 F-NMR研究3揭示了GPR 52的局部多态性。19 F-NMR数据还表明GPR 52-c17复合物和与G蛋白的三元复合物之间的细胞外配体结合口袋的局部差异。
Dear Editor, GPR52 is a class-A orphan GPCR, which has been reported as a target for treating Huntington’s disease, cognitive impairment, schizophrenia, and neuromuscular disorders. Previous structure determinations showed that GPR52 adopts an active conformation when bound to G-protein in the absence of any ligand. 1 A self-activation model was proposed, attributed to a built-in agonist motif embedded in the extracellular loop 2 (ECL2) near the orthosteric ligand binding pocket; this would also explain the high basal activity of GPR52. The synthetic ligand c17 is bound to a GPR52 side pocket, as shown in the co-crystal structure. 1 Recently, some new molecules with a similar chemical structure to c17 have entered pre-clinical trials for GPR52-related disorders. 2Structural and conformational dynamics studies of GPCRs are crucial for the screening of new ligands and understanding the molecular mechanisms of previously untapped drug targets. Here, we show a new cryo-electron microscopy (cryo-EM) structure of GPR52 bound with c17 at the extracellular side and G-protein at the intracellular side. 19F-NMR studies 3 of the complex by observation of the trifluoromethyl group in c17 (Figure 1A) revealed local polymorphisms in GPR52. 19F-NMR data also indicate localized differences in the extracellular ligand binding pocket between the GPR52–c17 complex and the ternary complex with the G-protein.
登录
查看更多内容
影响因子：
2.7
作者：
Liu, Dongsheng;Wuthrich, Kurt
通讯作者：
Wuthrich, Kurt
影响因子：
64.8
作者：
Lin, Xi;Li, Mingyue;Xu, Fei
通讯作者：
Xu, Fei
阿瑞匹坦与神经激肽 1 受体结合的 GPCR 大振幅动力学，通过 19 F-NMR 得到
DOI：
10.1073/pnas.2122682119
发表时间：
2022-04-12
影响因子：
11.1
作者：
通讯作者：
--
影响因子：
6.8
作者：
Didenko T;Liu JJ;Horst R;Stevens RC;Wüthrich K
通讯作者：
Wüthrich K