8UHB

Cryo-EM Structure of the Ro5256390-bound hTA1-Gs heterotrimer signaling complex

Summary for 8UHB

• Entry DOI: 10.2210/pdb8uhb/pdb
• EMDB information: 42268
• Descriptor: Soluble cytochrome b562,Beta-2 adrenergic receptor,Trace amine-associated receptor 1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, ... (6 entities in total)
• Functional Keywords: gpcr, signaling complex, trace amine-associated receptor, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 168035.26

Authors

Zilberg, G.,Warren, A.L.,Parpounas, A.K.,Wacker, D. (deposition date: 2023-10-08, release date: 2024-01-10, Last modification date: 2024-11-06)

Primary citation

Zilberg, G.,Parpounas, A.K.,Warren, A.L.,Yang, S.,Wacker, D.
Molecular basis of human trace amine-associated receptor 1 activation.
Nat Commun, 15:108-108, 2024

PubMed 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.

PubMed: 38168118
DOI: 10.1038/s41467-023-44601-4

Experimental method

ELECTRON MICROSCOPY (3.35 Å)