8jlo
Ulotaront(SEP-363856)-bound hTAAR1-Gs protein complex
Structural highlights
DiseaseGNAS2_HUMAN Pseudopseudohypoparathyroidism;Pseudohypoparathyroidism type 1A;Progressive osseous heteroplasia;Polyostotic fibrous dysplasia;Monostotic fibrous dysplasia;Pseudohypoparathyroidism type 1C;Pseudohypoparathyroidism type 1B;McCune-Albright syndrome. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Most affected individuals have defects in methylation of the gene. In some cases microdeletions involving the STX16 appear to cause loss of methylation at exon A/B of GNAS, resulting in PHP1B. Paternal uniparental isodisomy have also been observed. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionGNAS2_HUMAN Guanine nucleotide-binding proteins (G proteins) function as transducers in numerous signaling pathways controlled by G protein-coupled receptors (GPCRs) (PubMed:17110384). Signaling involves the activation of adenylyl cyclases, resulting in increased levels of the signaling molecule cAMP (PubMed:26206488, PubMed:8702665). GNAS functions downstream of several GPCRs, including beta-adrenergic receptors (PubMed:21488135). Stimulates the Ras signaling pathway via RAPGEF2 (PubMed:12391161).[1] [2] [3] [4] [5] Publication Abstract from PubMedTrace-amine-associated receptors (TAARs), a group of biogenic amine receptors, have essential roles in neurological and metabolic homeostasis(1). They recognize diverse endogenous trace amines and subsequently activate a range of G-protein-subtype signalling pathways(2,3). Notably, TAAR1 has emerged as a promising therapeutic target for treating psychiatric disorders(4,5). 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-HT(1A)R 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. Ligand recognition and G-protein coupling of trace amine receptor TAAR1.,Xu Z, Guo L, Yu J, Shen S, Wu C, Zhang W, Zhao C, Deng Y, Tian X, Feng Y, Hou H, Su L, Wang H, Guo S, Wang H, Wang K, Chen P, Zhao J, Zhang X, Yong X, Cheng L, Liu L, Yang S, Yang F, Wang X, Yu X, Xu Y, Sun JP, Yan W, Shao Z Nature. 2023 Dec;624(7992):672-681. doi: 10.1038/s41586-023-06804-z. Epub 2023 , Nov 7. PMID:37935376[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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