EMD-36626

Single-particle
3.65 Å
EMD-36626 Deposition: 20/06/2023
Map released: 15/11/2023
Last modified: 09/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-36626

Ulotaront(SEP-363856)-bound Serotonin 1A (5-HT1A) receptor-Gi complex

EMD-36626

Single-particle
3.65 Å
EMD-36626 Deposition: 20/06/2023
Map released: 15/11/2023
Last modified: 09/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens, Mus musculus
Sample: hTAAR1-bound T1AM in complex with Gs heterotrimer
Fitted models: 8jsp (Avg. Q-score: 0.411)

Deposition Authors: Xu Z , Guo LL, Zhao C , Shen SY, Sun JP , Shao ZH, Sun JP
Ligand recognition and G-protein coupling of trace amine receptor TAAR1.
PUBMED: 37935376
DOI: doi:10.1038/s41586-023-06804-z
ISSN: 1476-4687
ASTM: NATUAS
Abstract:
Trace-amine-associated receptors (TAARs), a group of biogenic amine receptors, have essential roles in neurological and metabolic homeostasis1. They recognize diverse endogenous trace amines and subsequently activate a range of G-protein-subtype signalling pathways2,3. Notably, TAAR1 has emerged as a promising therapeutic target for treating psychiatric disorders4,5. However, the molecular mechanisms underlying its ability to recognize different ligands remain largely unclear. Here we present nine cryo-electron microscopy structures, with eight showing human and mouse TAAR1 in a complex with an array of ligands, including the endogenous 3-iodothyronamine, two antipsychotic agents, the psychoactive drug amphetamine and two identified catecholamine agonists, and one showing 5-HT1AR in a complex with an antipsychotic agent. These structures reveal a rigid consensus binding motif in TAAR1 that binds to endogenous trace amine stimuli and two extended binding pockets that accommodate diverse chemotypes. Combined with mutational analysis, functional assays and molecular dynamic simulations, we elucidate the structural basis of drug polypharmacology and identify the species-specific differences between human and mouse TAAR1. Our study provides insights into the mechanism of ligand recognition and G-protein selectivity by TAAR1, which may help in the discovery of ligands or therapeutic strategies for neurological and metabolic disorders.