PT  - JOURNAL ARTICLE
AU  - Piotr Kosson
AU  - Jolanta Dyniewicz
AU  - Piotr F. J. Lipiński
AU  - Joanna Matalinska
AU  - Aleksandra Misicka
AU  - Andrzej J. Bojarski
AU  - Stefan Mordalski
TI  - Gα<sub>i</sub>-derived peptide binds the µ-opioid receptor
AID  - 10.1101/729244
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 729244
4099  - http://biorxiv.org/content/early/2019/08/08/729244.short
4100  - http://biorxiv.org/content/early/2019/08/08/729244.full
AB  - 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 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 Gαi-derived peptide of 12 amino acids binds the µ-opioid receptor (µOR) and acts as an allosteric modulator. The Gαi-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 Gαi 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.