Ligand recognition and G-protein coupling of trace amine receptor TAAR1

Zheng Xu, Lulu Guo, Jingjing Yu, Siyuan Shen, Chao Wu, Weifeng Zhang, Chang Zhao, Yue Deng, Xiaowen Tian, Yuying Feng, Hanlin Hou, Lantian Su, Hongshuang Wang, Shuo Guo, Heli Wang, Kexin Wang, Peipei Chen, Jie Zhao, Xiaoyu Zhang, Xihao Yong, Lin Cheng, Lunxu Liu, Shengyong Yang, Fan Yang, Xiaohui Wang, Xiao Yu (), Yunfei Xu (), Jin-Peng Sun (), Wei Yan () and Zhenhua Shao ()
Additional contact information
Zheng Xu: Sichuan University
Lulu Guo: Shandong University
Jingjing Yu: Sichuan University
Siyuan Shen: Sichuan University
Chao Wu: Sichuan University
Weifeng Zhang: Shandong University
Chang Zhao: Sichuan University
Yue Deng: Sichuan University
Xiaowen Tian: Sichuan University
Yuying Feng: Sichuan University
Hanlin Hou: Sichuan University
Lantian Su: Sichuan University
Hongshuang Wang: Chinese Academy of Sciences
Shuo Guo: Sichuan University
Heli Wang: Sichuan University
Kexin Wang: Sichuan University
Peipei Chen: Sichuan University
Jie Zhao: Sichuan University
Xiaoyu Zhang: Sichuan University
Xihao Yong: Sichuan University
Lin Cheng: University of Electronic Science and Technology of China
Lunxu Liu: Sichuan University
Shengyong Yang: Sichuan University
Fan Yang: Shandong University
Xiaohui Wang: Chinese Academy of Sciences
Xiao Yu: Shandong University
Yunfei Xu: Qilu Hospital of Shandong University
Jin-Peng Sun: Shandong University
Wei Yan: Sichuan University
Zhenhua Shao: Sichuan University

Nature, 2023, vol. 624, issue 7992, 672-681

Abstract: Abstract Trace-amine-associated receptors (TAARs), a group of biogenic amine receptors, have essential roles in neurological and metabolic homeostasis1. They recognize diverse endogenous trace amines and subsequently activate a range of G-protein-subtype signalling pathways2,3. Notably, TAAR1 has emerged as a promising therapeutic target for treating psychiatric disorders4,5. However, the molecular mechanisms underlying its ability to recognize different ligands remain largely unclear. Here we present nine cryo-electron microscopy structures, with eight showing human and mouse TAAR1 in a complex with an array of ligands, including the endogenous 3-iodothyronamine, two antipsychotic agents, the psychoactive drug amphetamine and two identified catecholamine agonists, and one showing 5-HT1AR in a complex with an antipsychotic agent. These structures reveal a rigid consensus binding motif in TAAR1 that binds to endogenous trace amine stimuli and two extended binding pockets that accommodate diverse chemotypes. Combined with mutational analysis, functional assays and molecular dynamic simulations, we elucidate the structural basis of drug polypharmacology and identify the species-specific differences between human and mouse TAAR1. Our study provides insights into the mechanism of ligand recognition and G-protein selectivity by TAAR1, which may help in the discovery of ligands or therapeutic strategies for neurological and metabolic disorders.

Date: 2023
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DOI: 10.1038/s41586-023-06804-z

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