8WCA

Cryo-EM structure of the PEA-bound hTAAR1-Gs complex

8WCA の概要

• エントリーDOI: 10.2210/pdb8wca/pdb
• EMDBエントリー: 37436
• 分子名称: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Trace amine-associated receptor 1, ... (6 entities in total)
• 機能のキーワード: pea, htaar1, 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: 157403.18

構造登録者

Rong, N.K.,Guo, L.L.,Zhang, M.H.,Li, Q.,Yang, F.,Sun, J.P. (登録日: 2023-09-11, 公開日: 2023-12-27, 最終更新日: 2024-11-13)

主引用文献

Shang, P.,Rong, N.,Jiang, J.J.,Cheng, J.,Zhang, M.H.,Kang, D.,Qi, L.,Guo, L.,Yang, G.M.,Liu, Q.,Zhou, Z.,Li, X.B.,Zhu, K.K.,Meng, Q.B.,Han, X.,Yan, W.,Kong, Y.,Yang, L.,Wang, X.,Lei, D.,Feng, X.,Liu, X.,Yu, X.,Wang, Y.,Li, Q.,Shao, Z.H.,Yang, F.,Sun, J.P.
Structural and signaling mechanisms of TAAR1 enabled preferential agonist design.
Cell, 186:5347-5362.e24, 2023

PubMed Abstract: Trace amine-associated receptor 1 (TAAR1) senses a spectrum of endogenous amine-containing metabolites (EAMs) to mediate diverse psychological functions and is useful for schizophrenia treatment without the side effects of catalepsy. Here, we systematically profiled the signaling properties of TAAR1 activation and present nine structures of TAAR1-Gs/Gq in complex with EAMs, clinical drugs, and synthetic compounds. These structures not only revealed the primary amine recognition pocket (PARP) harboring the conserved acidic D for conserved amine recognition and "twin" toggle switch for receptor activation but also elucidated that targeting specific residues in the second binding pocket (SBP) allowed modulation of signaling preference. In addition to traditional drug-induced Gs signaling, Gq activation by EAM or synthetic compounds is beneficial to schizophrenia treatment. Our results provided a structural and signaling framework for molecular recognition by TAAR1, which afforded structural templates and signal clues for TAAR1-targeted candidate compounds design.

PubMed: 37963465
DOI: 10.1016/j.cell.2023.10.014

実験手法

ELECTRON MICROSCOPY (3.48 Å)