Abstract
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.