Gαi-derived peptide binds the μ-opioid receptor

G protein-coupled receptors (GPCRs) transduce external stimuli into the cell by G proteins via an allosteric mechanism. Agonist binding to the receptor stimulates GDP/GTP exchange within the heterotrimeric G protein complex. Whereas recent structures of GPCR-G protein complexes revealed that the H5, S1 and S2 domains of G are involved in binding the active receptor, earlier studies showed that a short peptide analogue derived from the C-terminus (H5) of the G protein transducin (Gt) is sufficient to stabilize rhodopsin in an active form. Here, we show that a Gi-derived peptide of 12 amino acids binds the {micro}-opioid receptor ({micro}OR) and acts as an allosteric modulator. The Gi-derived peptide increases {micro}OR affinity for its agonist morphine in a dose-dependent way. These results indicate that the GPCR-G peptide interaction observed so far for only rhodopsin can be extrapolated to {micro}OR. In addition, we show that the C-terminal peptide of the Gi subunit is sufficient to stabilize the active conformation of the receptor. Our approach opens the possibility to investigate the GPCR-G protein interface with peptide modification.