Structural and signaling mechanisms of TAAR1 enabled preferential agonist design

Pan Shang; Naikang Rong; Jing-Jing Jiang; Jie Cheng; Ming-Hui Zhang; Dongwei Kang; Lei Qi; Lulu Guo; Gong-Ming Yang; Qun Liu; Zhenzhen Zhou; Xiao-Bing Li; Kong-Kai Zhu; Qing-Biao Meng; Xiang Han; Wenqi Yan; Yalei Kong; Lejin Yang; Xiaohui Wang; Dapeng Lei; Xin Feng; Xinyong Liu; Xiao Yu; Yue Wang; Qian Li; Zhen-Hua Shao; Fan Yang; Jin-Peng Sun

doi:10.1016/j.cell.2023.10.014

Structural and signaling mechanisms of TAAR1 enabled preferential agonist design

Cell. 2023 Nov 22;186(24):5347-5362.e24. doi: 10.1016/j.cell.2023.10.014. Epub 2023 Nov 13.

Authors

Pan Shang¹, Naikang Rong¹, Jing-Jing Jiang², Jie Cheng¹, Ming-Hui Zhang³, Dongwei Kang⁴, Lei Qi⁵, Lulu Guo⁶, Gong-Ming Yang², Qun Liu¹, Zhenzhen Zhou⁴, Xiao-Bing Li⁷, Kong-Kai Zhu⁶, Qing-Biao Meng², Xiang Han², Wenqi Yan², Yalei Kong⁸, Lejin Yang⁹, Xiaohui Wang¹⁰, Dapeng Lei², Xin Feng², Xinyong Liu⁴, Xiao Yu², Yue Wang¹¹, Qian Li¹², Zhen-Hua Shao¹³, Fan Yang¹⁴, Jin-Peng Sun¹⁵

Affiliations

¹ NHC Key Laboratory of Otorhinolaryngology, Qilu hospital and School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China; Advanced Medical Research Institute and Meili Lake Translational Research Park, Shandong University, Jinan, Shandong 250012, China.
² NHC Key Laboratory of Otorhinolaryngology, Qilu hospital and School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China.
³ Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
⁴ Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, Shandong 250012, China.
⁵ Advanced Medical Research Institute and Meili Lake Translational Research Park, Shandong University, Jinan, Shandong 250012, China; Biomedical Research Center for Structural Analysis, Shandong University, No.44 Wenhua Xi Road, Jinan, Shandong 250012, China.
⁶ Advanced Medical Research Institute and Meili Lake Translational Research Park, Shandong University, Jinan, Shandong 250012, China.
⁷ Medical Science and Technology Innovation Center, Shandong Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.
⁸ Songjiang Institute and Shanghai Songjiang District Central Hospital, Center for Brain Science in Shanghai Children's Medical Center, Department of Anatomy and Physiology, Ministry of Education, Shanghai Key Laboratory of Children's Environmental Health in Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁹ Department of Psychology, Qilu Hospital of Shandong University, Jinan, China.
¹⁰ Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China.
¹¹ Medical Science and Technology Innovation Center, Shandong Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China. Electronic address: wangyue@sdfmu.edu.cn.
¹² Songjiang Institute and Shanghai Songjiang District Central Hospital, Center for Brain Science in Shanghai Children's Medical Center, Department of Anatomy and Physiology, Ministry of Education, Shanghai Key Laboratory of Children's Environmental Health in Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: liqian@shsmu.edu.cn.
¹³ Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: zhenhuashao@scu.edu.cn.
¹⁴ NHC Key Laboratory of Otorhinolaryngology, Qilu hospital and School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China; Advanced Medical Research Institute and Meili Lake Translational Research Park, Shandong University, Jinan, Shandong 250012, China. Electronic address: yangfan1357@163.com.
¹⁵ NHC Key Laboratory of Otorhinolaryngology, Qilu hospital and School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China; Advanced Medical Research Institute and Meili Lake Translational Research Park, Shandong University, Jinan, Shandong 250012, China. Electronic address: sunjinpeng@sdu.edu.cn.

PMID: 37963465
DOI: 10.1016/j.cell.2023.10.014

Abstract

Trace amine-associated receptor 1 (TAAR1) senses a spectrum of endogenous amine-containing metabolites (EAMs) to mediate diverse psychological functions and is useful for schizophrenia treatment without the side effects of catalepsy. Here, we systematically profiled the signaling properties of TAAR1 activation and present nine structures of TAAR1-Gs/Gq in complex with EAMs, clinical drugs, and synthetic compounds. These structures not only revealed the primary amine recognition pocket (PARP) harboring the conserved acidic D^3.32 for conserved amine recognition and "twin" toggle switch for receptor activation but also elucidated that targeting specific residues in the second binding pocket (SBP) allowed modulation of signaling preference. In addition to traditional drug-induced Gs signaling, Gq activation by EAM or synthetic compounds is beneficial to schizophrenia treatment. Our results provided a structural and signaling framework for molecular recognition by TAAR1, which afforded structural templates and signal clues for TAAR1-targeted candidate compounds design.

Keywords: GPCR; TAAR1; cryo-EM structure; schizophrenia; trace amine-associated receptor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amines / metabolism
Humans
Receptors, G-Protein-Coupled* / metabolism
Schizophrenia / metabolism
Signal Transduction*

Substances

Amines
Receptors, G-Protein-Coupled
Trace amine-associated receptor 1