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Structural basis of selective cannabinoid CB2 receptor activation.
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.
Afiliação
  • Li X; iHuman Institute, ShanghaiTech University, Shanghai, 201210, China.
  • Chang H; iHuman Institute, ShanghaiTech University, Shanghai, 201210, China.
  • Bouma J; School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • de Paus LV; Division of Drug Discovery and Safety, Leiden Academic Center for Drug Research, Leiden University, Oncode Institute, Leiden, the Netherlands.
  • Mukhopadhyay P; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Oncode Institute, Leiden, the Netherlands.
  • Paloczi J; Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute of Health/National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA.
  • Mustafa M; Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute of Health/National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA.
  • van der Horst C; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
  • Kumar SS; Division of Drug Discovery and Safety, Leiden Academic Center for Drug Research, Leiden University, Oncode Institute, Leiden, the Netherlands.
  • Wu L; Division of Drug Discovery and Safety, Leiden Academic Center for Drug Research, Leiden University, Oncode Institute, Leiden, the Netherlands.
  • Yu Y; iHuman Institute, ShanghaiTech University, Shanghai, 201210, China.
  • van den Berg RJBHN; School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • Janssen APA; iHuman Institute, ShanghaiTech University, Shanghai, 201210, China.
  • Lichtman A; School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • Liu ZJ; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Oncode Institute, Leiden, the Netherlands.
  • Pacher P; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Oncode Institute, Leiden, the Netherlands.
  • van der Stelt M; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
  • Heitman LH; iHuman Institute, ShanghaiTech University, Shanghai, 201210, China. liuzhj@shanghaitech.edu.cn.
  • Hua T; School of Life Science and Technology, ShanghaiTech University, Shanghai, China. liuzhj@shanghaitech.edu.cn.
Nat Commun ; 14(1): 1447, 2023 03 15.
Article em En | MEDLINE | ID: mdl-36922494
ABSTRACT
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 GPCR drug design and sheds light on their activation by endogenous ligands.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Canabinoides / Agonistas de Receptores de Canabinoides Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: China
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Canabinoides / Agonistas de Receptores de Canabinoides Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: China