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

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.

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Figure 1: Overall view of the µ-OR structure.
Figure 2: Comparison of ligand-binding pockets.
Figure 3: Structural basis for morphinan ligand binding to the µ-OR.
Figure 4: µ-OR oligomeric arrangement.
Figure 5: The four-helix bundle interface.

Accession codes

Primary accessions

Protein Data Bank

Data deposits

Coordinates and structure factors for m-OR–T4L are deposited in the Protein Data Bank under accession code 4DKL.

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Acknowledgements

We acknowledge support from INSERM (S.G.), the Stanford Medical Scientist Training Program (A.M.), the National Science Foundation (A.C.K.), the Lundbeck Foundation (J.M.M.), the National Institutes of Health Grants NS028471 (B.K.K.) and DA031418 (B.K.K. and R.K.S.), and the Mathers Foundation (B.K.K. and W.I.W.).

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Authors

Contributions

A.M., A.C.K. and S.G. designed experiments, performed research and analysed data. T.S.K. and F.S.T. expressed and purified receptor. J.M.M. performed preliminary biochemical experiments with wild-type µ-OR. R.K.S. contributed to the effort of µ-OR crystallization and writing of the manuscript. W.I.W. supervised diffraction data analysis and model refinement. L.P. built the tetramer model and helped with the analysis of the dimer interfaces. A.M., A.C.K., S.G. and B.K.K. prepared the manuscript. S.G. and B.K.K. supervised the research.

Corresponding authors

Correspondence to Brian K. Kobilka or Sébastien Granier.

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The authors declare no competing financial interests.

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Manglik, A., Kruse, A., Kobilka, T. et al. Crystal structure of the µ-opioid receptor bound to a morphinan antagonist. Nature 485, 321–326 (2012). https://doi.org/10.1038/nature10954

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