Leiden University Scholarly Publications

Persistent URL of this record https://hdl.handle.net/1887/3590023

In Collections

This item can be found in the following collections:

Li, X.; Chang, H.; Bouma, J.; Paus, L.V. de; Mukhopadhyay, P.; Paloczi, J.; ... ; Hua, T. (2023)

Structural basis of selective cannabinoid CB2 receptor activation

Article / Letter to editor
Cannabinoid CB2 receptor (CB2R) 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 CB2R agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate the selective CB2R activation by binding kinetics, site-directed mutagenesis, and cryo-EM studies. We identify key residues for CB2R 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 CB2R activation by selective agonists and highlights the role of lipophilicity in CB2R engagement. This may have implications for...Show moreCannabinoid CB2 receptor (CB2R) 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 CB2R agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate the selective CB2R activation by binding kinetics, site-directed mutagenesis, and cryo-EM studies. We identify key residues for CB2R 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 CB2R activation by selective agonists and highlights the role of lipophilicity in CB2R engagement. This may have implications for GPCR drug design and sheds light on their activation by endogenous ligands.Show less
All authors
Li, X.; Chang, H.; Bouma, J.; Paus, L.V. de; Mukhopadhyay, P.; Paloczi, J.; Mustafa, M.; Horst, C. van der; Kumar, S.S.; Wu, L.; Yu, Y.; Berg, R.J.B.H.N. van den; Janssen, A.P.A.; Lichtman, A.; Liu, Z.J.; Pacher, P.; Stelt, M. van der; Heitman, L.H.; Hua, T.
Date
2023-03-15
Journal
Nature Communications
Volume
14
Issue
1
DOI
doi:10.1038/s41467-023-37112-9