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Nature. 2020 Mar;579(7797):152-157. doi: 10.1038/s41586-020-2019-0. Epub 2020 Feb 19.

Structural basis of ligand recognition and self-activation of orphan GPR52.

Lin X1,2,3,4, Li M2,3,4, Wang N1,2,3,4, Wu Y1, Luo Z5, Guo S6, Han GW7, Li S8,9, Yue Y1, Wei X2,3,4, Xie X2,6, Chen Y2,3,4, Zhao S1,2, Wu J10,11,12, Lei M13,14,15, Xu F16,17,18.

Author information

1
iHuman Institute, ShanghaiTech University, Shanghai, China.
2
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
3
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
4
University of Chinese Academy of Sciences, Beijing, China.
5
Institute of Molecular Enzymology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
6
CAS Key Laboratory of Receptor Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
7
Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA, USA.
8
Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
9
Shanghai Institute of Precision Medicine, Shanghai, China.
10
Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. wujian@shsmu.edu.cn.
11
Shanghai Institute of Precision Medicine, Shanghai, China. wujian@shsmu.edu.cn.
12
Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China. wujian@shsmu.edu.cn.
13
Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. leim@shsmu.edu.cn.
14
Shanghai Institute of Precision Medicine, Shanghai, China. leim@shsmu.edu.cn.
15
Key Laboratory of Cell Differentiation and Apoptosis, Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China. leim@shsmu.edu.cn.
16
iHuman Institute, ShanghaiTech University, Shanghai, China. xufei@shanghaitech.edu.cn.
17
School of Life Science and Technology, ShanghaiTech University, Shanghai, China. xufei@shanghaitech.edu.cn.
18
Centre for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China. xufei@shanghaitech.edu.cn.

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.

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PMID:
32076264
DOI:
10.1038/s41586-020-2019-0
[Indexed for MEDLINE]

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