1. Academic Validation
  2. Ligand recognition and G protein coupling of trace amine receptor TAAR1

Ligand recognition and G protein coupling of trace amine receptor TAAR1

  • Nature. 2023 Nov 7. doi: 10.1038/s41586-023-06804-z.
Zheng Xu # 1 Lulu Guo # 2 Jingjing Yu # 1 Siyuan Shen # 1 Chao Wu # 1 Weifeng Zhang # 3 Chang Zhao # 1 Yue Deng 1 Xiaowen Tian 1 Yuying Feng 1 Hanlin Hou 1 Lantian Su 1 Hongshuang Wang 4 Shuo Guo 1 Heli Wang 1 Kexin Wang 1 Peipei Chen 1 Jie Zhao 1 Xiaoyu Zhang 1 Xihao Yong 1 Lin Cheng 5 Lunxu Liu 6 Shengyong Yang 1 Fan Yang 2 7 Xiaohui Wang 4 8 9 Xiao Yu 10 Yunfei Xu 11 Jin-Peng Sun 12 13 Wei Yan 14 Zhenhua Shao 15 16
Affiliations

Affiliations

  • 1 Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 2 Advanced Medical Research Institute, Meili Lake Translational Research Park, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • 3 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China.
  • 4 Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
  • 5 Department of Otolaryngology Head and Neck Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
  • 6 Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 7 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China.
  • 8 School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, China.
  • 9 Beijing National Laboratory for Molecular Sciences, Beijing, China.
  • 10 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China. yuxiao@sdu.edu.cn.
  • 11 Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China. xuyunfei1988@126.com.
  • 12 Advanced Medical Research Institute, Meili Lake Translational Research Park, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. sunjinpeng@sdu.edu.cn.
  • 13 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China. sunjinpeng@sdu.edu.cn.
  • 14 Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China. weiyan2018@scu.edu.cn.
  • 15 Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China. zhenhuashao@scu.edu.cn.
  • 16 Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, China. zhenhuashao@scu.edu.cn.
  • # Contributed equally.
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.

Figures
Products