8GUT

Cryo-EM structure of LEI-CB2-Gi complex

Summary for 8GUT

• Entry DOI: 10.2210/pdb8gut/pdb
• EMDB information: 34279
• Descriptor: 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 subunit gamma, ... (6 entities in total)
• Functional Keywords: gpcr, g protein, cryo-em, membrane protein, structural protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 151473.93

Authors

Liu, Z.J.,Hua, T.,Li, X.T.,Chang, H.,Wu, L.J. (deposition date: 2022-09-13, release date: 2023-05-10, Last modification date: 2024-11-06)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (2.98 Å)