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Newly identified structures of trace-amine associated receptor-1 (TAAR1) will aid discovery of next generation neuropsychiatric drugs

Molecular Psychiatry (2024)Cite this article

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The trace-amine associated receptor-1 (TAAR1) is a member of the G-protein coupled receptor (GPCR) receptor family and is widely distributed across the brain and gastrointestinal system and functions in a variety of neuronal processes [1,2,3]. A range of endogenous trace amines (TA) activate TAAR1 signalling pathways through G protein subtypes [3]. Several neuropsychiatric disorders, including schizophrenia, depression, drug addiction, attention deficit hyperactive disorder (ADHD) and metabolic disorders are associated with TAAR1 [3,4,5]. An emerging new class of antipsychotic agents, TAAR1 agonists, show promise for treating schizophrenia (Ulotaront – US FDA Breakthrough therapy status) and other neuropsychiatric conditions [5].

Xu et al. resolved eight cryo-electron microscopy structures of TAAR1 (human and mouse) with a range of ligands, including the endogenous 3-iodothyronamine (T1AM), potential antipsychotic agents (ulotaront, ralmitaront), psychoactive drug (amphetamine), and two catecholamine agonists (fenoldopam, A77636) [8]. Most of the Cryo-EM studies were focused on the hTAAR1 complexes with different agonists. Moreover, structural differences in ulotaront recognition were also investigated in 5-HT1A receptor structure to better understand polypharmacology. The study identified that essentially, hTAAR1 and mTAAR1 were structurally similar and closely resembled other activated GPCR complexes. In general, the investigated agonists bound to the orthosteric binding site of TAAR1 forming contacts with the transmembrane (TM), TM3, TM6, TM7 and the second extracellular loop (ECL2) adopting a ‘lid’ conformation, shielding the pocket. The residues D3.32-S3.36-Y7.43 motif formed the ‘pocket 1’ and was mainly associated with agonist binding, whereas the ‘pocket 2’constituted of TM3, TM6 and ECL2 and was responsible for receptor activation. The non-conservation of residues in pocket 2 was proposed as a sign of divergence in ligand recognition. The most important amino acid residue involved in the recognition of TAAR1 agonist was D3.32 (Asp103) of the pocket 1. Mutagenesis and radioligand binding studies confirmed the importance of the residue D3.32 as essential for ligand binding. This residue forms salt-bridge interaction with the amine group of TAAR1 agonist. Likewise, the role of other residues such as S3.36 in ligand binding were also verified. The importance of several of these residues were consistent with the previously proposed computational models of TAAR1 (e.g., models of TAAR1-ulotaront complex) [7]. Additionally, mutagenesis studies were performed to demonstrate the importance of non-conserved residues within TAAR1’s orthosteric site in determining ligand specificity across species. As part of this study, 22 ligands from a synthetic organic database were screened and two catecholamine derivatives, fenoldopam (peripheral vasodilator for hypertension treatment) and A77636, were identified as agonists of the TAAR1 receptor, proposing a strategy for potential drug repurposing. Structure analysis revealed biologically active amines bind using a core binding mode, where the residues participating in the core mode were relatively rigid. Extended binding modes were also noted for different chemicals. For instance, in ralmitaront bound TAAR1 structure, a substantial displacement was observed in certain residues (F4.56, T5.45, and S5.46), resulting in an extended pocket 3 to accommodate the pyrazole ring. By contrast, fenoldopam and A77636 bound TAAR1 showed displacement around the extracellular region of the receptor, creating another extended pocket (pocket 4) to accommodate the hydroxyphenyl and adamantane group, respectively, with a notable conformational change at ECL2. Using a bioluminescence resonance energy transfer (BRET) assay, this study measured TAAR1 G-protein-subtype activation in response to different ligands in both hTAAR1 and mTAAR1. The ligands included biologically active amines β-phenylethylamine (β-PEA), T1AM, trimethylamine (TMA), cadaverine (CAD) and isoamylamine (IAA), a xenobiotic metabolite cyclohexylamine (CHA), two synthetic agonists (ulotaront, ralmitaront) and amphetamine (AMPH). The cellular assay revealed certain agonists (β-PEA, T1AM and ulotaront) showed specific activity towards the Gαs (stimulatory; activates protein kinase A pathway) subtype, while some acted as specific agonists (CHA and IAA) for TAAR1–Gαq (stimulatory; activates the phospholipase C) signalling, and CAD exclusively activated the Gαi (inhibitory) signalling of TAAR1. By using alanine scanning mutagenesis, the importance of different residues associated with the activation of different G proteins downstream of TAAR1 was examined, leading to the identification of key residues that determine the subtype selectivity of G proteins. Additionally, the study provides valuable insights into pharmacological differences between mTAAR1 and hTAAR1 as well as the applicability of mouse models in drug discovery.

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Fig. 1: Structural basis of ligand recognition in TAAR1.

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Authors and Affiliations

  1. Discipline of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia

    Pramod C. Nair & Britto Shajan

  2. Flinders Health and Medical Research Institute (FHMRI) College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia

    Pramod C. Nair

  3. Department of Psychiatry, Monash University, Clayton Campus, Melbourne, VIC, Australia

    Tarun Bastiampillai

  4. Discipline of Psychiatry, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia

    Tarun Bastiampillai

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PCN conceptualised and wrote the first draft of the manuscript. BS and TB contributed to writing the manuscript.

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Correspondence to Pramod C. Nair.

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Nair, P.C., Shajan, B. & Bastiampillai, T. Newly identified structures of trace-amine associated receptor-1 (TAAR1) will aid discovery of next generation neuropsychiatric drugs. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02466-z

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