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TitleMolecular basis of human trace amine-associated receptor 1 activation.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 108, Year 2024
Publish dateJan 2, 2024
AuthorsGregory Zilberg / Alexandra K Parpounas / Audrey L Warren / Shifan Yang / Daniel Wacker /
PubMed AbstractThe 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 ...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.
External linksNat Commun / PubMed:38168118 / PubMed Central
MethodsEM (single particle)
Resolution3.35 Å
Structure data

42268

8uhb

EMDB-42268, PDB-8uhb:
Cryo-EM Structure of the Ro5256390-bound hTA1-Gs heterotrimer signaling complex
Method: EM (single particle) / Resolution: 3.35 Å

Chemicals

ChemComp-WV8:
(2R,4S)-4-[(2S)-2-phenylbutyl]-1,3-oxazolidin-2-amine

Source
  • homo sapiens (human)
  • rattus norvegicus (Norway rat)
  • lama glama (llama)
KeywordsMEMBRANE PROTEIN / GPCR / Signaling Complex / Trace Amine-associated Receptor

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