Recognition of methamphetamine and other amines by trace amine receptor TAAR1

Heng Liu, You Zheng, Yue Wang, Yumeng Wang, Xinheng He, Peiyu Xu, Sijie Huang, Qingning Yuan, Xinyue Zhang, Ling Wang, Kexin Jiang, Hong Chen, Zhen Li, Wenbin Liu (), Sheng Wang (), H. Eric Xu () and Fei Xu ()
Additional contact information
Heng Liu: Chinese Academy of Sciences
You Zheng: ShanghaiTech University
Yue Wang: Chinese Academy of Sciences
Yumeng Wang: University of Chinese Academy of Sciences
Xinheng He: Chinese Academy of Sciences
Peiyu Xu: Chinese Academy of Sciences
Sijie Huang: Chinese Academy of Sciences
Qingning Yuan: Chinese Academy of Sciences
Xinyue Zhang: Chinese Academy of Sciences
Ling Wang: ShanghaiTech University
Kexin Jiang: ShanghaiTech University
Hong Chen: Shanghai Research Institute of Criminal Science and Technology
Zhen Li: Chinese Academy of Sciences
Wenbin Liu: Shanghai Research Institute of Criminal Science and Technology
Sheng Wang: Chinese Academy of Sciences
H. Eric Xu: Chinese Academy of Sciences
Fei Xu: ShanghaiTech University

Nature, 2023, vol. 624, issue 7992, 663-671

Abstract: 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 addiction2,4,5. 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-HT1AR (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.

Date: 2023
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DOI: 10.1038/s41586-023-06775-1

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