Journal Article

Structure of the µ-opioid receptor–Gi protein complex

Matile, Hugues, Dror, Ron O., Hu, Hongli, Hilger, Daniel, Latorraca, Naomi R., Schertler, Gebhard F. X., Granier, Sebastien, Koehl, Antoine, Manglik, Aashish, Paggi, Joseph M., Dawson, Roger, Kobilka, Brian K., Qu, Qianhui, Maeda, Shoji, Zhang, Yan, Weis, William I., Skiniotis, Georgios

2018

Overview

The μ-opioid receptor (μOR) is a G-protein-coupled receptor (GPCR) and the target of most clinically and recreationally used opioids. The induced positive effects of analgesia and euphoria are mediated by μOR signalling through the adenylyl cyclase-inhibiting heterotrimeric G protein G i . Here we present the 3.5 Å resolution cryo-electron microscopy structure of the μOR bound to the agonist peptide DAMGO and nucleotide-free G i . DAMGO occupies the morphinan ligand pocket, with its N terminus interacting with conserved receptor residues and its C terminus engaging regions important for opioid-ligand selectivity. Comparison of the μOR–G i complex to previously determined structures of other GPCRs bound to the stimulatory G protein G s reveals differences in the position of transmembrane receptor helix 6 and in the interactions between the G protein α-subunit and the receptor core. Together, these results shed light on the structural features that contribute to the G i protein-coupling specificity of the µOR. A cryo-electron structure of the µ-opioid receptor in complex with the peptide agonist DAMGO and the inhibitory G protein G i reveals structural determinants of its G protein-binding specificity.

• Publisher: Nature Publishing Group UK
• Subject: 101/28 / 631/154/436/2387 / 631/535/1258/1259 / 82 / 82/1 / 82/80 / 82/83 / Humanities and Social Sciences / multidisciplinary / Science / Science (multidisciplinary)