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Structure paper

TitleStructural basis of selective cannabinoid CB receptor activation.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 1447, Year 2023
Publish dateMar 15, 2023
AuthorsXiaoting Li / Hao Chang / Jara Bouma / Laura V de Paus / Partha Mukhopadhyay / Janos Paloczi / Mohammed Mustafa / Cas van der Horst / Sanjay Sunil Kumar / Lijie Wu / Yanan Yu / Richard J B H N van den Berg / Antonius P A Janssen / Aron Lichtman / Zhi-Jie Liu / Pal Pacher / Mario van der Stelt / Laura H Heitman / Tian Hua /
PubMed AbstractCannabinoid 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, ...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.
External linksNat Commun / PubMed:36922494 / PubMed Central
MethodsEM (single particle)
Resolution2.84 - 3.08 Å
Structure data

34276

8guq

EMDB-34276, PDB-8guq:
Cryo-EM structure of CB2-G protein complex
Method: EM (single particle) / Resolution: 3.08 Å

34277

8gur

EMDB-34277, PDB-8gur:
Cryo-EM structure of CP-CB2-G protein complex
Method: EM (single particle) / Resolution: 2.84 Å

34278

8gus

EMDB-34278, PDB-8gus:
Cryo-EM structure of HU-CB2-G protein complex
Method: EM (single particle) / Resolution: 2.97 Å

34279

8gut

EMDB-34279, PDB-8gut:
Cryo-EM structure of LEI-CB2-Gi complex
Method: EM (single particle) / Resolution: 2.98 Å

Chemicals

ChemComp-KNF:
Olorinab

ChemComp-9GF:
2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol

ChemComp-KO3:
[(1~{S},4~{S},5~{S})-4-[2,6-dimethoxy-4-(2-methyloctan-2-yl)phenyl]-6,6-dimethyl-2-bicyclo[3.1.1]hept-2-enyl]methanol

ChemComp-KO8:
1-[[4-[5-fluoranyl-6-[(oxan-4-ylamino)methyl]pyridin-2-yl]phenyl]methyl]-3-(2-methylpropyl)imidazolidine-2,4-dione

Source
  • homo sapiens (human)
KeywordsSTRUCTURAL PROTEIN / GPCR / G protein / cryo-EM / membrane protein

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