7V69

Cryo-EM structure of a class A GPCR-G protein complex

7V69 の概要

• エントリーDOI: 10.2210/pdb7v69/pdb
• EMDBエントリー: 31738 31739 31740
• 分子名称: Guanine nucleotide-binding protein G(i) subunit alpha-1, 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, ... (5 entities in total)
• 機能のキーワード: complex, 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: 152545.98

構造登録者

Wang, J.J.,Wu, M.,Wu, L.J.,Hua, T.,Liu, Z.J.,Wang, T. (登録日: 2021-08-20, 公開日: 2022-05-11, 最終更新日: 2024-11-06)

主引用文献

Wang, J.,Wu, M.,Chen, Z.,Wu, L.,Wang, T.,Cao, D.,Wang, H.,Liu, S.,Xu, Y.,Li, F.,Liu, J.,Chen, N.,Zhao, S.,Cheng, J.,Wang, S.,Hua, T.
The unconventional activation of the muscarinic acetylcholine receptor M4R by diverse ligands.
Nat Commun, 13:2855-2855, 2022

PubMed Abstract: Muscarinic acetylcholine receptors (mAChRs) respond to the neurotransmitter acetylcholine and play important roles in human nervous system. Muscarinic receptor 4 (M4R) is a promising drug target for treating neurological and mental disorders, such as Alzheimer's disease and schizophrenia. However, the lack of understanding on M4R's activation by subtype selective agonists hinders its therapeutic applications. Here, we report the structural characterization of M4R selective allosteric agonist, compound-110, as well as agonist iperoxo and positive allosteric modulator LY2119620. Our cryo-electron microscopy structures of compound-110, iperoxo or iperoxo-LY2119620 bound M4R-G complex reveal their different interaction modes and activation mechanisms of M4R, and the M4R-ip-LY-G structure validates the cooperativity between iperoxo and LY2119620 on M4R. Through the comparative structural and pharmacological analysis, compound-110 mostly occupies the allosteric binding pocket with vertical binding pose. Such a binding and activation mode facilitates its allostersic selectivity and agonist profile. In addition, in our schizophrenia-mimic mouse model study, compound-110 shows antipsychotic activity with low extrapyramidal side effects. Thus, this study provides structural insights to develop next-generation antipsychotic drugs selectively targeting on mAChRs subtypes.

PubMed: 35606397
DOI: 10.1038/s41467-022-30595-y

実験手法

ELECTRON MICROSCOPY (3.4 Å)