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8JLP

Ralmitaront(RO-6889450)-bound hTAAR1-Gs protein complex

8JLP の概要
エントリーDOI10.2210/pdb8jlp/pdb
EMDBエントリー36403
分子名称Gs, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Soluble cytochrome b562,Trace amine-associated receptor 1, ... (5 entities in total)
機能のキーワードcomplex, agonist, membrane protein
由来する生物種Homo sapiens
詳細
タンパク質・核酸の鎖数4
化学式量合計144563.37
構造登録者
Xu, Z.,Guo, L.L.,Zhao, C.,Shen, S.Y.,Sun, J.P.,Shao, Z.H. (登録日: 2023-06-02, 公開日: 2023-11-15, 最終更新日: 2024-01-03)
主引用文献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, J.P.,Yan, W.,Shao, Z.
Ligand recognition and G-protein coupling of trace amine receptor TAAR1.
Nature, 624:672-681, 2023
Cited by
PubMed Abstract: Trace-amine-associated receptors (TAARs), a group of biogenic amine receptors, have essential roles in neurological and metabolic homeostasis. They recognize diverse endogenous trace amines and subsequently activate a range of G-protein-subtype signalling pathways. Notably, TAAR1 has emerged as a promising therapeutic target for treating psychiatric disorders. 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-HTR 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.
PubMed: 37935376
DOI: 10.1038/s41586-023-06804-z
主引用文献が同じPDBエントリー
実験手法
ELECTRON MICROSCOPY (3.23 Å)
構造検証レポート
Validation report summary of 8jlp
検証レポート(詳細版)ダウンロードをダウンロード

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件を2024-10-30に公開中

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