Gα(i)-derived peptide binds the µ-opioid receptor

BACKGROUND: 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 Gα are involved in binding the active receptor, earlier studies showed that a short peptide analog derived from the C-terminus (H5) of the G protein transducin (G(t)) is sufficient to stabilize rhodopsin in an active form. METHODS: We have used Molecular Dynamics simulations along with biological evaluation by means of radio-ligand binding assay to study the interactions between Gα(i)-derived peptide (G-peptide) and the µ-opioid receptor (µOR). RESULTS: Here, we show that a Gα(i)-derived peptide of 12 amino acids binds the µ-opioid receptor and acts as an allosteric modulator. The Gα(i)-derived peptide increases µOR affinity for its agonist morphine in a dose-dependent way. CONCLUSIONS: These results indicate that the GPCR–Gα peptide interaction observed so far for only rhodopsin can be extrapolated to µOR. In addition, we show that the C-terminal peptide of the Gα(i) 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43440-023-00457-5.