The G protein-first activation mechanism of opioid receptors by Gi protein and agonists

Abstract We report the G protein-first mechanism for activation of protein-coupled receptors (GPCR) three closest subtypes opioid (OR), ?OR, ?OR and ?OR. find that they couple to inactive Gi protein-bound guanosine diphosphate (GDP) prior agonist binding. The protein forms anchors intracellular loops apo-?OR, apo-?OR apo-?OR, inducing opening cytoplasmic region form a pre-activated state holds in place until binds. Then, binds ?OR already complexed with protein, trigger G?i open up tightly coupled GDP binding site, making accessible GTP exchange, an essential step signalling. show alone cannot ?OR ?OR, requiring by itself. consider this may apply other Class A GPCRs. However, ?OR, can encourage recruitment. Thus, mediated favourably proceed either ligand-first or mechanisms.