Allosterism in the adenosine A2A and cannabinoid CB2 heteromer

• DOI: 10.1111/bph.16502
• Publication Date: 2024-07-24T07:21:32Z
• Authors: Claudia Llinas de...; Iu Raïch; Angel Gonzalez; Jaume Lillo; Nil Casajuana‐Martin; Rafael Franco; Leonardo Pardo; Gemma Navarro
• Keywords: Allosteric modulator

Abstract Background and Purpose Allosterism is a regulatory mechanism for GPCRs that can be attained by ligand‐binding or protein–protein interactions with another GPCR. We have studied the influence of dimer interface on allosteric properties A 2A receptor CB 2 heteromer. Experimental Approach evaluated cAMP production, phosphorylation signal‐regulated kinases (pERK1/2), label‐free dynamic mass redistribution, β‐arrestin recruitment bimolecular fluorescence complementation assays in absence presence synthetic peptides disrupt formation Molecular simulations provided converging evidence heteromeric influences R–CB R Key Results Apo blocks agonist‐induced signalling R. The disruptive peptides, amino acid sequence transmembrane (TM) 6 R, facilitate activation, suggesting allosterically prevents outward movement TM G protein binding. Significantly, binding selective antagonist SCH 58261 to also facilitated activation Conclusions Implications It proposed heteromer contains distinct dimerization interfaces govern its functional properties. molecular between protomers interconverted from apo agonist‐bound blocking mainly 1/7 antagonist‐bound facilitating independent opening intracellular cavities These novel results shed light different type extend repertoire GPCR signalling.