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Ligand recognition and G protein coupling of trace amine receptor TAAR1

Abstract

Trace amine-associated receptors (TAARs), a group of biogenic amine receptors, play pivotal roles in neurological and metabolic homeostasis1. They recognize diverse endogenous trace amines (ETAs) and subsequently activate a range of G protein subtype signaling 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 elusive. Here, we present nine cryo-electron microscopy (EM) structures, with eight showing human and mouse TAAR1 in 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 depicting 5-HT1AR in complex with an antipsychotic agent. These structures reveal a rigid consensus binding motif in TAAR1 that binds to ETAs 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 aid the discovery of ligands or therapeutic strategies for neurological and metabolic disorders.

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Author notes

  1. These authors contributed equally: Zheng Xu, Lulu Guo, Jingjing Yu, Siyuan Shen, Chao Wu, Weifeng Zhang, Chang Zhao

Authors and Affiliations

  1. Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Zheng Xu, Jingjing Yu, Siyuan Shen, Chao Wu, Chang Zhao, Yue Deng, Xiaowen Tian, Yuying Feng, Hanlin Hou, Lantian Su, Shuo Guo, Heli Wang, Kexin Wang, Peipei Chen, Jie Zhao, Xiaoyu Zhang, Xihao Yong, Shengyong Yang, Wei Yan & Zhenhua Shao

  2. Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, China

    Zhenhua Shao

  3. Advanced Medical Research Institute, Meili Lake Translational Research Park, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China

    Lulu Guo, Fan Yang & Jin-Peng Sun

  4. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China

    Weifeng Zhang & Xiao Yu

  5. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China

    Fan Yang & Jin-Peng Sun

  6. Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China

    Yunfei Xu

  7. Department of Otolaryngology Head and Neck Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China

    Lin Cheng

  8. Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Lunxu Liu

  9. Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China

    Hongshuang Wang & Xiaohui Wang

  10. School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, China

    Xiaohui Wang

  11. Beijing National Laboratory for Molecular Sciences, Beijing, China

    Xiaohui Wang

Authors

  1. Zheng Xu
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  2. Lulu Guo
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  29. Wei Yan
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  30. Zhenhua Shao
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Corresponding authors

Correspondence to
Xiao Yu, Yunfei Xu, Jin-Peng Sun, Wei Yan or Zhenhua Shao.

Supplementary information

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This Supplementary Information file includes: Supplementary Figs. 1-19, Supplementary Tables 1-5, and Supplementary Methods.

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Xu, Z., Guo, L., Yu, J. et al. Ligand recognition and G protein coupling of trace amine receptor TAAR1.
Nature (2023). https://doi.org/10.1038/s41586-023-06804-z

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  • Received: 08 June 2023

  • Accepted: 31 October 2023

  • Published: 07 November 2023

  • DOI: https://doi.org/10.1038/s41586-023-06804-z

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