Structural and functional insights into the G protein-coupled receptors: CB1 and CB2

Abstract

The cannabinoid receptors CB1 and CB2 mediate a variety of physiological processes and continue to be explored as desirable drug targets. Both receptors are activated by the endogenous endocannabinoids and the psychoactive components of marijuana. Over the years, many efforts have been made to make selective ligands; however, the high degree of homology between cannabinoid receptor subtypes introduces challenges in studying either receptor in isolation. Recent advancements in structure biology have resulted in a surge of high-resolution structures, enriching our knowledge and understanding of receptor structure and function. In this review, of recent cannabinoid receptor structures, key features of the inactive and active state CB1 and CB2 are presented. These structures will provide additional insight into the modulation and signaling mechanism of cannabinoid receptors CB1 and CB2 and aid in the development of future therapeutics.

Keywords: G-protein-coupled receptors; cannabinoids; cryo-electron microscopy; crystallography.

Figure 1.. Class A GPCR general structure.

A ligand-bound GPCR interacting with the heterotrimeric G protein.

Figure 2.. Comparing the confirmational changes of key molecular switches between the antagonist- and agonist-bound CB1 and CB2.

(A) Antagonist-bound CB1 receptor (PDB: 5TGZ) in dark blue with the agonist-bound CB1 (PDB: 6KPG) in grey. (B) Antagonist-bound CB2 receptor (PDB: 5ZTY) in brown, overlayed with the agonist-bound CB2 structure (PDB: 6KPF) in beige. Arrows within each panel indicate shifts from the inactive to active state receptor.