Format

Send to

Choose Destination
Nature. 2018 Jun;558(7711):547-552. doi: 10.1038/s41586-018-0219-7. Epub 2018 Jun 13.

Structure of the µ-opioid receptor-Gi protein complex.

Author information

1
Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
2
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
3
Department of Computer Science, Stanford University, Stanford, CA, USA.
4
Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA.
5
Biophysics Program, Stanford University, Stanford, CA, USA.
6
Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F.Hoffmann-La Roche, Basel, Switzerland.
7
Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland.
8
Department of Biology, ETH Zürich, Zürich, Switzerland.
9
Institut de Génomique Fonctionnelle, INSERM, Montpellier, France.
10
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA. Aashish.Manglik@ucsf.edu.
11
Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USA. Aashish.Manglik@ucsf.edu.
12
Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. yiorgo@stanford.edu.
13
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. yiorgo@stanford.edu.
14
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. kobilka@stanford.edu.

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.

PMID:
29899455
PMCID:
PMC6317904
DOI:
10.1038/s41586-018-0219-7
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center