8E9X

CryoEM structure of miniGo-coupled hM4Di in complex with DCZ

8E9X の概要

• エントリーDOI: 10.2210/pdb8e9x/pdb
• EMDBエントリー: 27967
• 分子名称: Muscarinic acetylcholine receptor M4, miniGo, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (6 entities in total)
• 機能のキーワード: gpcr, dcz, active state, membrane protein, hm4di, dreadd
• 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: 136504.05

構造登録者

Zhang, S.,Fay, J.F.,Roth, B.L. (登録日: 2022-08-27, 公開日: 2022-11-30, 最終更新日: 2025-05-14)

主引用文献

Zhang, S.,Gumpper, R.H.,Huang, X.P.,Liu, Y.,Krumm, B.E.,Cao, C.,Fay, J.F.,Roth, B.L.
Molecular basis for selective activation of DREADD-based chemogenetics.
Nature, 612:354-362, 2022

PubMed Abstract: Designer receptors exclusively activated by designer drugs (DREADDs) represent a powerful chemogenetic technology for the remote control of neuronal activity and cellular signalling. The muscarinic receptor-based DREADDs are the most widely used chemogenetic tools in neuroscience research. The G-coupled DREADD (hM3Dq) is used to enhance neuronal activity, whereas the G-coupled DREADD (hM4Di) is utilized to inhibit neuronal activity. Here we report four DREADD-related cryogenic electron microscopy high-resolution structures: a hM3Dq-miniG complex and a hM4Di-miniG complex bound to deschloroclozapine; a hM3Dq-miniG complex bound to clozapine-N-oxide; and a hM3R-miniG complex bound to iperoxo. Complemented with mutagenesis, functional and computational simulation data, our structures reveal key details of the recognition of DREADD chemogenetic actuators and the molecular basis for activation. These findings should accelerate the structure-guided discovery of next-generation chemogenetic tools.

PubMed: 36450989
DOI: 10.1038/s41586-022-05489-0

実験手法

ELECTRON MICROSCOPY (2.7 Å)