Homodimerization of CB2cannabinoid receptor triggered by a bivalent ligand enhances cellular signaling

Abstract

ABSTRACTG protein-coupled receptors (GPCRs) exist within a landscape of interconvertible conformational states and in dynamic equilibrium between monomers and higher-order oligomers, both influenced by ligand binding. Here, we have shown that a homobivalent ligand formed by equal chromenopyrazole moieties as pharmacophores, connected by 14 methylene units, can modulate the dynamics of the cannabinoid CB2receptor (CB2R) homodimerization by simultaneously binding both protomers of the CB2R-CB2R homodimer. Computational and pharmacological experimentals showed that one of the ligand pharmacophores binds to the orthosteric site of one protomer, and the other pharmacophore to a membrane-oriented pocket between transmembranes 1 and 7 of the partner protomer. This provides unique pharmacological properties, such as increased potency in Gibinding and increased recruitment of β-arrestin. Thus, by modulating dimerization dynamics, it may be possible to fine-tune CB2R activity with potentially improved therapeutic outcomes.HIGHLIGHTSA homobivalent ligand of CB2R (PM369) modulates the dynamics of receptor homodimerizationPM369 binds to the orthosteric site of one protomer and to a complementary, membrane-facing, site of the other protomerPM369 triggers CB2R homodimerization via the TM 1/7 interface that provides unique pharmacological propertiesPM369 potentiates signaling, increased potency in Gibinding and increased recruitment of β-arrestinThese results highlight new approaches to control GPCR signalingGRAPHICAL ABSTRACT