Crystal structure of the µ-opioid receptor bound to a morphinan antagonist

Nature. 2012 Mar 21;485(7398):321-6. doi: 10.1038/nature10954.

Abstract

Opium is one of the world's oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical opioids produce analgesia as well as many undesirable side effects (sedation, apnoea and dependence) by binding to and activating the G-protein-coupled µ-opioid receptor (µ-OR) in the central nervous system. Here we describe the 2.8 Å crystal structure of the mouse µ-OR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most G-protein-coupled receptors published so far, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the µ-OR crystallizes as a two-fold symmetrical dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into opioid receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction.

Publication types

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

MeSH terms

  • Animals
  • Binding Sites
  • Crystallography, X-Ray
  • Ligands
  • Mice
  • Models, Molecular
  • Morphinans / chemistry*
  • Morphinans / metabolism
  • Morphinans / pharmacology
  • Protein Conformation
  • Protein Multimerization
  • Receptors, Opioid, mu / antagonists & inhibitors*
  • Receptors, Opioid, mu / chemistry*
  • Receptors, Opioid, mu / metabolism
  • Solvents / chemistry

Substances

  • Ligands
  • Morphinans
  • Receptors, Opioid, mu
  • Solvents

Associated data

  • PDB/4DKL