Gα_i-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 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.

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).

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.

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.