Structure of the µ-opioid receptor–Gi protein complex

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, Sebastien Granier, William I. Weis, Ron O. Dror, Aashish Manglik (), Georgios Skiniotis () and Brian K. Kobilka ()
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Antoine Koehl: Stanford University School of Medicine
Hongli Hu: Stanford University School of Medicine
Shoji Maeda: Stanford University School of Medicine
Yan Zhang: Stanford University School of Medicine
Qianhui Qu: Stanford University School of Medicine
Joseph M. Paggi: Stanford University School of Medicine
Naomi R. Latorraca: Stanford University School of Medicine
Daniel Hilger: Stanford University School of Medicine
Roger Dawson: F.Hoffmann–La Roche
Hugues Matile: F.Hoffmann–La Roche
Gebhard F. X. Schertler: Paul Scherrer Institute
Sebastien Granier: INSERM
William I. Weis: Stanford University School of Medicine
Ron O. Dror: Stanford University School of Medicine
Aashish Manglik: University of California San Francisco
Georgios Skiniotis: Stanford University School of Medicine
Brian K. Kobilka: Stanford University School of Medicine

Nature, 2018, vol. 558, issue 7711, 547-552

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41586-018-0219-7

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