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.

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.

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