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Structure of the µ-opioid receptor–Gi protein complex

2018; Nature Portfolio; Volume: 558; Issue: 7711 Linguagem: Inglês

10.1038/s41586-018-0219-7

1476-4687

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

Mass Spectrometry Techniques and Applications

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 Gi. Here we present the 3.5 Å resolution cryo-electron microscopy structure of the μOR bound to the agonist peptide DAMGO and nucleotide-free Gi. 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–Gi complex to previously determined structures of other GPCRs bound to the stimulatory G protein Gs 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 Gi 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 Gi reveals structural determinants of its G protein-binding specificity.