8GHV

Cannabinoid Receptor 1-G Protein Complex

8GHV の概要

• エントリーDOI: 10.2210/pdb8ghv/pdb
• EMDBエントリー: 40052 40057 40058
• 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, 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: 169786.29

構造登録者

Krishna Kumar, K.,Robertson, M.J.,Skiniotis, G.,Kobilka, B.K. (登録日: 2023-03-12, 公開日: 2023-05-24, 最終更新日: 2024-10-09)

主引用文献

Krishna Kumar, K.,Robertson, M.J.,Thadhani, E.,Wang, H.,Suomivuori, C.M.,Powers, A.S.,Ji, L.,Nikas, S.P.,Dror, R.O.,Inoue, A.,Makriyannis, A.,Skiniotis, G.,Kobilka, B.
Structural basis for activation of CB1 by an endocannabinoid analog.
Nat Commun, 14:2672-2672, 2023

PubMed Abstract: Endocannabinoids (eCBs) are endogenous ligands of the cannabinoid receptor 1 (CB1), a G protein-coupled receptor that regulates a number of therapeutically relevant physiological responses. Hence, understanding the structural and functional consequences of eCB-CB1 interactions has important implications for designing effective drugs targeting this receptor. To characterize the molecular details of eCB interaction with CB1, we utilized AMG315, an analog of the eCB anandamide to determine the structure of the AMG315-bound CB1 signaling complex. Compared to previous structures, the ligand binding pocket shows some differences. Using docking, molecular dynamics simulations, and signaling assays we investigated the functional consequences of ligand interactions with the "toggle switch" residues F200 and W356. Further, we show that ligand-TM2 interactions drive changes to residues on the intracellular side of TM2 and are a determinant of efficacy in activating G protein. These intracellular TM2 rearrangements are unique to CB1 and are exploited by a CB1-specific allosteric modulator.

PubMed: 37160876
DOI: 10.1038/s41467-023-37864-4

実験手法

ELECTRON MICROSCOPY (2.8 Å)