학술논문
Structural basis of selective cannabinoid CB2 receptor activation
Document Type
Original Paper
Author
Li, Xiaoting; Chang, Hao; Bouma, Jara; de Paus, Laura V.; Mukhopadhyay, Partha; Paloczi, Janos; Mustafa, Mohammed; van der Horst, Cas; Kumar, Sanjay Sunil; Wu, Lijie; Yu, Yanan; van den Berg, Richard J. B. H. N.; Janssen, Antonius P. A.; Lichtman, Aron; Liu, Zhi-Jie; Pacher, Pal; van der Stelt, Mario; Heitman, Laura H.; Hua, Tian
Source
Nature Communications. 14(1)
Subject
Language
English
ISSN
2041-1723
Abstract
Cannabinoid CB2 receptor (CB2 R) 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 CB2 R agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate the selective CB2 R activation by binding kinetics, site-directed mutagenesis, and cryo-EM studies. We identify key residues for CB2 R 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 CB2 R activation by selective agonists and highlights the role of lipophilicity in CB2 R engagement. This may have implications for GPCR drug design and sheds light on their activation by endogenous ligands.
Cannabinoid CB2 receptor (CB2 R) agonists are investigated as therapeutic agents in the clinic. Here, authors report the discovery of LEI-102, a CB2 R agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate selective CB2 R activation.
Cannabinoid CB