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

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 () and Fei Xu ()
Additional contact information
Xi Lin: ShanghaiTech University
Mingyue Li: ShanghaiTech University
Niandong Wang: ShanghaiTech University
Yiran Wu: ShanghaiTech University
Zhipu Luo: Soochow University
Shimeng Guo: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Gye-Won Han: University of Southern California
Shaobai Li: Shanghai Jiao Tong University School of Medicine
Yang Yue: ShanghaiTech University
Xiaohu Wei: ShanghaiTech University
Xin Xie: ShanghaiTech University
Yong Chen: ShanghaiTech University
Suwen Zhao: ShanghaiTech University
Jian Wu: Shanghai Jiao Tong University School of Medicine
Ming Lei: Shanghai Jiao Tong University School of Medicine
Fei Xu: ShanghaiTech University

Nature, 2020, vol. 579, issue 7797, 152-157

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2019-0

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