8W8A

Cryo-EM structure of the RO5256390-TAAR1 complex

8W8A の概要

• エントリーDOI: 10.2210/pdb8w8a/pdb
• EMDBエントリー: 37350
• 分子名称: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (7 entities in total)
• 機能のキーワード: taar1, r05256390, gpcr, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 128700.46

構造登録者

Liu, H.,Zheng, Y.,Wang, Y.,Wang, Y.,He, X.,Xu, P.,Huang, S.,Yuan, Q.,Zhang, X.,Wang, S.,Xu, H.E.,Xu, F. (登録日: 2023-09-01, 公開日: 2023-11-22, 最終更新日: 2024-11-20)

主引用文献

Liu, H.,Zheng, Y.,Wang, Y.,Wang, Y.,He, X.,Xu, P.,Huang, S.,Yuan, Q.,Zhang, X.,Wang, L.,Jiang, K.,Chen, H.,Li, Z.,Liu, W.,Wang, S.,Xu, H.E.,Xu, F.
Recognition of methamphetamine and other amines by trace amine receptor TAAR1.
Nature, 624:663-671, 2023

PubMed Abstract: Trace amine-associated receptor 1 (TAAR1), the founding member of a nine-member family of trace amine receptors, is responsible for recognizing a range of biogenic amines in the brain, including the endogenous β-phenylethylamine (β-PEA) as well as methamphetamine, an abused substance that has posed a severe threat to human health and society. Given its unique physiological role in the brain, TAAR1 is also an emerging target for a range of neurological disorders including schizophrenia, depression and drug addiction. Here we report structures of human TAAR1-G-protein complexes bound to methamphetamine and β-PEA as well as complexes bound to RO5256390, a TAAR1-selective agonist, and SEP-363856, a clinical-stage dual agonist for TAAR1 and serotonin receptor 5-HTR (refs. ). Together with systematic mutagenesis and functional studies, the structures reveal the molecular basis of methamphetamine recognition and underlying mechanisms of ligand selectivity and polypharmacology between TAAR1 and other monoamine receptors. We identify a lid-like extracellular loop 2 helix/loop structure and a hydrogen-bonding network in the ligand-binding pockets, which may contribute to the ligand recognition in TAAR1. These findings shed light on the ligand recognition mode and activation mechanism for TAAR1 and should guide the development of next-generation therapeutics for drug addiction and various neurological disorders.

PubMed: 37935377
DOI: 10.1038/s41586-023-06775-1

実験手法

ELECTRON MICROSCOPY (2.8 Å)