8gut | pdb_00008gut
Cryo-EM structure of LEI-CB2-Gi complex
Structural highlights
FunctionGNAI1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.[1] [2] Publication Abstract from PubMedCannabinoid CB(2) receptor (CB(2)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 CB(2)R agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate the selective CB(2)R activation by binding kinetics, site-directed mutagenesis, and cryo-EM studies. We identify key residues for CB(2)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 CB(2)R activation by selective agonists and highlights the role of lipophilicity in CB(2)R engagement. This may have implications for GPCR drug design and sheds light on their activation by endogenous ligands. Structural basis of selective cannabinoid CB(2) receptor activation.,Li X, Chang H, Bouma J, de Paus LV, Mukhopadhyay P, Paloczi J, Mustafa M, van der Horst C, Kumar SS, Wu L, Yu Y, van den Berg RJBHN, Janssen APA, Lichtman A, Liu ZJ, Pacher P, van der Stelt M, Heitman LH, Hua T Nat Commun. 2023 Mar 15;14(1):1447. doi: 10.1038/s41467-023-37112-9. PMID:36922494[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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