Recognition of methamphetamine and other amines by trace amine receptor TAAR1 PMID: 37935377

GLP-1 and Obesity Research

2026-08-18

Recognition of methamphetamine and other amines by trace amine receptor TAAR1

Nature. 2023 Dec;624(7992):663-671. doi: 10.1038/s41586-023-06775-1.

Heng Liu ^# ¹ , You Zheng ^# ² , Yue Wang ^# ¹ ³ , Yumeng Wang ^# ³ ⁴ , Xinheng He ¹ ³ , Peiyu Xu ¹ ³ , Sijie Huang ¹ ³ , Qingning Yuan ¹ ⁵ , Xinyue Zhang ¹ ⁶ , Ling Wang ² , Kexin Jiang ² , Hong Chen ⁷ ⁸ , Zhen Li ¹ ⁶ , Wenbin Liu ⁹ ¹⁰ , Sheng Wang ¹¹ ¹² , H Eric Xu ¹³ ¹⁴ ¹⁵ , Fei Xu ¹⁶ ¹⁷

Affiliations

1. The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
2. iHuman Institute, School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
3. University of Chinese Academy of Sciences, Beijing, China.
4. State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecule Cell Science, Chinese Academy of Sciences, Shanghai, China.
5. The Shanghai Advanced Electron Microscope Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
6. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
7. Shanghai Key Laboratory of Crime Scene Evidence, Shanghai Research Institute of Criminal Science and Technology, Shanghai, China.
8. Shanghai Yuansi Standard Science and Technology Co., Ltd, Shanghai, China.
9. Shanghai Key Laboratory of Crime Scene Evidence, Shanghai Research Institute of Criminal Science and Technology, Shanghai, China. [email protected].
10. Shanghai Yuansi Standard Science and Technology Co., Ltd, Shanghai, China. [email protected].
11. State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecule Cell Science, Chinese Academy of Sciences, Shanghai, China. [email protected].
12. Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. [email protected].
13. The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
14. University of Chinese Academy of Sciences, Beijing, China. [email protected].
15. School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
16. iHuman Institute, School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
17. Shanghai Clinical Research and Trial Center, Shanghai, China. [email protected].
# Contributed equally.

Abstract

Trace amine-associated receptor 1 (TAAR1), the founding member of a nine-member family of trace amine receptors, is responsible for recognizing a range of biogenic amines in the brain, including the endogenous β-phenylethylamine (β-PEA)¹ as well as methamphetamine², an abused substance that has posed a severe threat to human health and society³. Given its unique physiological role in the brain, TAAR1 is also an emerging target for a range of neurological disorders including schizophrenia, depression and drug addiction^2,4,5. Here we report structures of human TAAR1-G-protein complexes bound to methamphetamine and β-PEA as well as complexes bound to RO5256390, a TAAR1-selective agonist, and SEP-363856, a clinical-stage dual agonist for TAAR1 and serotonin receptor 5-HT_1AR (refs. ^6,7). Together with systematic mutagenesis and functional studies, the structures reveal the molecular basis of methamphetamine recognition and underlying mechanisms of ligand selectivity and polypharmacology between TAAR1 and Other monoamine receptors. We identify a lid-like extracellular loop 2 helix/loop structure and a hydrogen-bonding network in the ligand-binding pockets, which may contribute to the ligand recognition in TAAR1. These findings shed light on the ligand recognition mode and activation mechanism for TAAR1 and should guide the development of next-generation therapeutics for drug addiction and various neurological disorders.