Structural Basis of Selective Cannabinoid CB Receptor Activation

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Mar 16

PMID 36922494

Authors

Xiaoting 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

Affiliations

Soon will be listed here.

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.

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