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Recognition of methamphetamine and other amines by trace amine receptor TAAR1

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 methamphetamine (METH)2, 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 METH 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-HT1AR6,7. Together with systematic mutagenesis and functional studies, the structures reveal the molecular basis of METH recognition and underlying mechanisms of ligand selectivity and polypharmacology between TAAR1 and other monoamine receptors. We identify a lid-like ECL2 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.

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Author notes

  1. These authors contributed equally: Heng Liu, You Zheng, Yue Wang, Yumeng Wang

Authors and Affiliations

  1. The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

    Heng Liu, Yue Wang, Xinheng He, Peiyu Xu, Sijie Huang, Qingning Yuan, Xinyue Zhang, Zhen Li & H. Eric Xu

  2. iHuman Institute, School of Life Science and Technology, ShanghaiTech University, Shanghai, China

    You Zheng, Ling Wang, Kexin Jiang & Fei Xu

  3. University of Chinese Academy of Sciences, Beijing, China

    Yue Wang, Yumeng Wang, Xinheng He, Peiyu Xu, Sijie Huang & H. Eric Xu

  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

    Yumeng Wang & Sheng Wang

  5. The Shanghai Advanced Electron Microscope Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

    Qingning Yuan

  6. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China

    Xinyue Zhang & Zhen Li

  7. Shanghai Key Laboratory of Crime Scene Evidence, Shanghai Research Institute of Criminal Science and Technology, 803 Zhongshan North 1st Road, Shanghai, China

    Hong Chen & Wenbin Liu

  8. Shanghai Yuansi Standard Science and Technology Co., Ltd, 196 Ouyang Road, Shanghai, China

    Hong Chen & Wenbin Liu

  9. 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

    Sheng Wang

  10. School of Life Science and Technology, ShanghaiTech University, Shanghai, China

    H. Eric Xu

  11. Shanghai Clinical Research and Trial Center, Shanghai, China

    Fei Xu

Authors

  1. Heng Liu
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  2. You Zheng
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Correspondence to
Wenbin Liu, Sheng Wang, H. Eric Xu or Fei Xu.

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Liu, H., Zheng, Y., Wang, Y. et al. Recognition of methamphetamine and other amines by trace amine receptor TAAR1.
Nature (2023). https://doi.org/10.1038/s41586-023-06775-1

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  • Received: 05 May 2023

  • Accepted: 20 October 2023

  • Published: 07 November 2023

  • DOI: https://doi.org/10.1038/s41586-023-06775-1

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