8GUR

Cryo-EM structure of CP-CB2-G protein complex

8GUR の概要

• エントリーDOI: 10.2210/pdb8gur/pdb
• EMDBエントリー: 34277
• 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, ... (6 entities in total)
• 機能のキーワード: gpcr, g protein, cryo-em, membrane protein, structural 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: 153577.29

構造登録者

Wu, L.J.,Hua, T.,Liu, Z.J.,Li, X.T.,Chang, H. (登録日: 2022-09-13, 公開日: 2023-05-10, 最終更新日: 2024-10-23)

主引用文献

Li, X.,Chang, H.,Bouma, J.,de Paus, L.V.,Mukhopadhyay, P.,Paloczi, J.,Mustafa, M.,van der Horst, C.,Kumar, S.S.,Wu, L.,Yu, Y.,van den Berg, R.J.B.H.N.,Janssen, A.P.A.,Lichtman, A.,Liu, Z.J.,Pacher, P.,van der Stelt, M.,Heitman, L.H.,Hua, T.
Structural basis of selective cannabinoid CB 2 receptor activation.
Nat Commun, 14:1447-1447, 2023

PubMed Abstract: Cannabinoid CB receptor (CBR) agonists are investigated as therapeutic agents in the clinic. However, their molecular mode-of-action is not fully understood. Here, we report the discovery of LEI-102, a CBR agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate the selective CBR activation by binding kinetics, site-directed mutagenesis, and cryo-EM studies. We identify key residues for CBR activation. Highly lipophilic HU308 and the endocannabinoids, but not the more polar LEI-102, APD371, and CP55,940, reach the binding pocket through a membrane channel in TM1-TM7. Favorable physico-chemical properties of LEI-102 enable oral efficacy in a chemotherapy-induced nephropathy model. This study delineates the molecular mechanism of CBR activation by selective agonists and highlights the role of lipophilicity in CBR engagement. This may have implications for GPCR drug design and sheds light on their activation by endogenous ligands.

PubMed: 36922494
DOI: 10.1038/s41467-023-37112-9

実験手法

ELECTRON MICROSCOPY (2.84 Å)