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Molecular basis of human trace amine-associated receptor 1 activation

Author

Listed:
  • Gregory Zilberg

    (Icahn School of Medicine at Mount Sinai)

  • Alexandra K. Parpounas

    (Icahn School of Medicine at Mount Sinai)

  • Audrey L. Warren

    (Icahn School of Medicine at Mount Sinai)

  • Shifan Yang

    (Icahn School of Medicine at Mount Sinai)

  • Daniel Wacker

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

Abstract

The human trace amine-associated receptor 1 (hTAAR1, hTA1) is a key regulator of monoaminergic neurotransmission and the actions of psychostimulants. Despite preclinical research demonstrating its tractability as a drug target, its molecular mechanisms of activation remain unclear. Moreover, poorly understood pharmacological differences between rodent and human TA1 complicate the translation of findings from preclinical disease models into novel pharmacotherapies. To elucidate hTA1’s mechanisms on the molecular scale and investigate the underpinnings of its divergent pharmacology from rodent orthologs, we herein report the structure of the human TA1 receptor in complex with a Gαs heterotrimer. Our structure reveals shared structural elements with other TAARs, as well as with its closest monoaminergic orthologue, the serotonin receptor 5-HT4R. We further find that a single mutation dramatically shifts the selectivity of hTA1 towards that of its rodent orthologues, and report on the effects of substituting residues to those found in serotonin and dopamine receptors. Strikingly, we also discover that the atypical antipsychotic medication and pan-monoaminergic antagonist asenapine potently and efficaciously activates hTA1. Together our studies provide detailed insight into hTA1 structure and function, contrast its molecular pharmacology with that of related receptors, and uncover off-target activities of monoaminergic drugs at hTA1.

Suggested Citation

  • Gregory Zilberg & Alexandra K. Parpounas & Audrey L. Warren & Shifan Yang & Daniel Wacker, 2024. "Molecular basis of human trace amine-associated receptor 1 activation," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44601-4
    DOI: 10.1038/s41467-023-44601-4
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    1. Lulu Guo & Jie Cheng & Shuo Lian & Qun Liu & Yan Lu & Yuan Zheng & Kongkai Zhu & Minghui Zhang & Yalei Kong & Chao Zhang & Naikang Rong & Yuming Zhuang & Guoxing Fang & Jingjing Jiang & Tianyao Zhang , 2023. "Structural basis of amine odorant perception by a mammal olfactory receptor," Nature, Nature, vol. 618(7963), pages 193-200, June.
    2. A. J. Venkatakrishnan & Xavier Deupi & Guillaume Lebon & Christopher G. Tate & Gebhard F. Schertler & M. Madan Babu, 2013. "Molecular signatures of G-protein-coupled receptors," Nature, Nature, vol. 494(7436), pages 185-194, February.
    3. Stephen D. Liberles & Linda B. Buck, 2006. "A second class of chemosensory receptors in the olfactory epithelium," Nature, Nature, vol. 442(7103), pages 645-650, August.
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    1. Anastasiia Gusach & Yang Lee & Armin Nikpour Khoshgrudi & Elizaveta Mukhaleva & Ning Ma & Eline J. Koers & Qingchao Chen & Patricia C. Edwards & Fanglu Huang & Jonathan Kim & Filippo Mancia & Dmitry B, 2024. "Molecular recognition of an odorant by the murine trace amine-associated receptor TAAR7f," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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