8jsp | pdb_00008jsp
Ulotaront(SEP-363856)-bound Serotonin 1A (5-HT1A) receptor-Gi complex
Structural highlights
FunctionGNAI1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.[1] [2] Publication Abstract from PubMedTrace amine-associated receptors (TAARs), a group of biogenic amine receptors, play pivotal roles in neurological and metabolic homeostasis(1). They recognize diverse endogenous trace amines (ETAs) and subsequently activate a range of G protein subtype signaling 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 elusive. Here, we present nine cryo-electron microscopy (EM) structures, with eight showing human and mouse TAAR1 in 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 depicting 5-HT(1A)R in complex with an antipsychotic agent. These structures reveal a rigid consensus binding motif in TAAR1 that binds to ETAs 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 aid 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 Nov 7. doi: 10.1038/s41586-023-06804-z. PMID:37935376[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
