上海科技大学徐菲、上海交通大学医学院附属第九人民医院精准医学研究院雷鸣和Jian Wu课题组合作揭示了GPR52配体识别和自我激活的结构基础。2020年2月19日出版的《自然》杂志在线发表了这项成果。

研究人员解析了高分辨率人类GPR52蛋白在三种状态下的结构：无配体状态、G_s耦合的自激活状态和与潜在变构配体结合的状态。综合这三种状态下的结构，研究人员发现：细胞外环2占据了正性结合口袋，并作为内置激动剂起作用，赋予GPR52内在高水平的基础活性。在无外部激活剂的情况下，将G_s与GPR52偶联，GPR52将达到完全激活状态。

该受体还具有配体结合的侧袋。 对GPR52的结构和功能的阐明可以增进人类对其它自激活GPCR的理解，能够鉴定内源和工具配体，并指导靶向GPR52药物的开发。

据介绍，GPR52是一种在大脑中高表达的A类孤儿G蛋白偶联受体，是治疗亨廷顿病和多种精神疾病的潜在治疗靶点。GPR52信号通路的病理性功能障碍主要是由异源三聚体G_s蛋白引起的，但尚不清楚GPR52和G_s如何偶联以进行信号转导以及是否需要天然配体或其他激活信号。

附：英文原文

Title: Structural basis of ligand recognition and self-activation of orphan GPR52

Author: Xi Lin, Mingyue Li, Niandong Wang, Yiran Wu, Zhipu Luo, Shimeng Guo, Gye-Won Han, Shaobai Li, Yang Yue, Xiaohu Wei, Xin Xie, Yong Chen, Suwen Zhao, Jian Wu, Ming Lei, Fei Xu

Issue&Volume: 2020-02-19

Abstract: 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 disorders1,2. Pathological malfunction of GPR52 signalling occurs primarily through the heterotrimeric Gs protein2, but it is unclear how GPR52 and Gs 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 Gs-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 GPR523. A fully active state is achieved when Gs 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.

DOI: 10.1038/s41586-020-2019-0

Source: https://www.nature.com/articles/s41586-020-2019-0