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; Brian K Kobilka

doi:10.1038/s41586-018-0219-7

Structure of the µ-opioid receptor-G_i protein complex

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

Authors

Antoine Koehl^#¹, Hongli Hu^#^{1

2}, Shoji Maeda^#², Yan Zhang^{1

2}, Qianhui Qu^{1

2}, Joseph M Paggi^{1

2

3

4}, Naomi R Latorraca^{1

2

3

4

5}, Daniel Hilger², Roger Dawson⁶, Hugues Matile⁶, Gebhard F X Schertler^{7

8}, Sebastien Granier⁹, William I Weis^{1

2}, Ron O Dror^{1

2

3

4

5}, Aashish Manglik^{10

11}, Georgios Skiniotis^{12

13}, Brian K Kobilka¹⁴

Affiliations

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.

^# Contributed equally.

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 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Binding Sites
Cryoelectron Microscopy*
Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology
Female
GTP-Binding Protein alpha Subunits, Gi-Go / chemistry
GTP-Binding Protein alpha Subunits, Gi-Go / metabolism*
GTP-Binding Protein alpha Subunits, Gi-Go / ultrastructure*
GTP-Binding Protein alpha Subunits, Gs / chemistry
GTP-Binding Protein alpha Subunits, Gs / metabolism
Humans
Ligands
Mice
Mice, Inbred BALB C
Molecular Dynamics Simulation
Morphinans / chemistry
Morphinans / metabolism
Protein Stability / drug effects
Receptors, Adrenergic, beta-2 / chemistry
Receptors, Adrenergic, beta-2 / metabolism
Receptors, Opioid, mu / agonists
Receptors, Opioid, mu / chemistry
Receptors, Opioid, mu / metabolism*
Receptors, Opioid, mu / ultrastructure*
Substrate Specificity

Substances

Ligands
Morphinans
Receptors, Adrenergic, beta-2
Receptors, Opioid, mu
Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
GTP-Binding Protein alpha Subunits, Gi-Go
GTP-Binding Protein alpha Subunits, Gs

Abstract

Publication types

MeSH terms

Substances

Grants and funding