Structural basis of ligand recognition and self-activation of orphan GPR52
Structural basis of ligand recognition and self-activation of orphan GPR52
复制标题
DOI：
10.1038/s41586-020-2019-0
复制
发表时间：
2020-02-19
期刊：
影响因子：
64.8
通讯作者：
Xu, Fei
中科院分区：
文献类型：
--
作者：
Lin, Xi;Li, Mingyue;Xu, Fei
无配体的孤儿G蛋白偶联受体GPR52的结构，G蛋白偶联和配体结合状态揭示了细胞外环2占据正构结合口袋，并作为内置激动剂激活受体。偶联受体，其在脑中高度表达并且代表用于治疗亨廷顿病和几种亨廷顿病的有希望的治疗靶点。精神疾病（1，2）。GPR52信号传导的病理性功能障碍主要通过异源三聚体G（s）蛋白发生（2），但目前尚不清楚GPR52和G（s）如何偶联进行信号转导，以及是否需要天然配体或其他激活输入。在这里，我们提出了三种状态下的人GPR52的高分辨率结构：无配体状态，G（s）偶联的自激活状态和潜在的变构配体结合状态。总之，我们的结构揭示了细胞外环2占据了正构结合口袋，并作为内置激动剂发挥作用，赋予GPR52固有的高水平基础活性（3）。当G（s）在不存在外部激动剂的情况下与GPR52偶联时，达到完全活性状态。该受体还具有用于配体结合的侧袋。这些对GPR52结构和功能的见解可以提高我们对其他自激活GPCR的理解，使内源性和工具配体的鉴定成为可能，并指导靶向GPR52的药物发现工作。
Structures of the orphan G-protein-coupled receptor GPR52 in ligand-free, G-protein-coupled and ligand-bound states reveal that extracellular loop 2 occupies the orthosteric binding pocket and functions as a built-in agonist to activate the receptor.GPR52 is a class-A orphan G-protein-coupled receptor that is highly expressed in the brain and represents a promising therapeutic target for the treatment of Huntington's disease and several psychiatric disorders(1,2). Pathological malfunction of GPR52 signalling occurs primarily through the heterotrimeric G(s) protein(2), but it is unclear how GPR52 and G(s) couple for signal transduction and whether a native ligand or other activating input is required. Here we present the high-resolution structures of human GPR52 in three states: a ligand-free state, a G(s)-coupled self-activation state and a potential allosteric ligand-bound state. Together, our structures reveal that extracellular loop 2 occupies the orthosteric binding pocket and operates as a built-in agonist, conferring an intrinsically high level of basal activity to GPR52(3). A fully active state is achieved when G(s) is coupled to GPR52 in the absence of an external agonist. The receptor also features a side pocket for ligand binding. These insights into the structure and function of GPR52 could improve our understanding of other self-activated GPCRs, enable the identification of endogenous and tool ligands, and guide drug discovery efforts that target GPR52.