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

Author

Listed:
  • Aashish Manglik

    (Stanford University School of Medicine)

  • Andrew C. Kruse

    (Stanford University School of Medicine)

  • Tong Sun Kobilka

    (Stanford University School of Medicine)

  • Foon Sun Thian

    (Stanford University School of Medicine)

  • Jesper M. Mathiesen

    (Stanford University School of Medicine)

  • Roger K. Sunahara

    (University of Michigan Medical School)

  • Leonardo Pardo

    (Laboratori de Medicina Computacional, Unitat de Bioestadística, Universitat Autònoma de Barcelona)

  • William I. Weis

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Brian K. Kobilka

    (Stanford University School of Medicine)

  • Sébastien Granier

    (Stanford University School of Medicine
    CNRS UMR 5203, INSERM U661, and Université Montpellier 1 et 2, Institut de Génomique Fonctionnelle)

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.

Suggested Citation

  • Aashish Manglik & Andrew C. Kruse & Tong Sun Kobilka & Foon Sun Thian & Jesper M. Mathiesen & Roger K. Sunahara & Leonardo Pardo & William I. Weis & Brian K. Kobilka & Sébastien Granier, 2012. "Crystal structure of the µ-opioid receptor bound to a morphinan antagonist," Nature, Nature, vol. 485(7398), pages 321-326, May.
    • Handle: RePEc:nat:nature:v:485:y:2012:i:7398:d:10.1038_nature10954
    DOI: 10.1038/nature10954
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    Cited by:

    1. Wenli Zhao & Wenru Zhang & Mu Wang & Minmin Lu & Shutian Chen & Tingting Tang & Gisela Schnapp & Holger Wagner & Albert Brennauer & Cuiying Yi & Xiaojing Chu & Shuo Han & Beili Wu & Qiang Zhao, 2022. "Ligand recognition and activation of neuromedin U receptor 2," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. Md Tariqul Haque Tuhin & Dengpan Liang & Fang Liu & Hala Aldawod & Toufiq Ul Amin & Joshua S. Ho & Rasha Emara & Arjun D. Patel & Melanie A. Felmlee & Miki S. Park & James A. Uchizono & Mamoun M. Alha, 2022. "Peripherally restricted transthyretin-based delivery system for probes and therapeutics avoiding opioid-related side effects," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Song-Meng Wang & Yan-Fang Wang & Liping Huang & Li-Shuo Zheng & Hao Nian & Yu-Tao Zheng & Huan Yao & Wei Jiang & Xiaoping Wang & Liu-Pan Yang, 2023. "Chiral recognition of neutral guests by chiral naphthotubes with a bis-thiourea endo-functionalized cavity," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    4. Shun Kaneko & Shunsuke Imai & Tomomi Uchikubo-Kamo & Tamao Hisano & Nobuaki Asao & Mikako Shirouzu & Ichio Shimada, 2024. "Structural and dynamic insights into the activation of the μ-opioid receptor by an allosteric modulator," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    5. Justine S. Paradis & Xiang Feng & Brigitte Murat & Robert E. Jefferson & Badr Sokrat & Martyna Szpakowska & Mireille Hogue & Nick D. Bergkamp & Franziska M. Heydenreich & Martine J. Smit & Andy Chevig, 2022. "Computationally designed GPCR quaternary structures bias signaling pathway activation," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    6. Jun Yu & Amit Kumar & Xuefeng Zhang & Charlotte Martin & Kevin Van holsbeeck & Pierre Raia & Antoine Koehl & Toon Laeremans & Jan Steyaert & Aashish Manglik & Steven Ballet & Andreas Boland & Miriam S, 2024. "Structural basis of μ-opioid receptor targeting by a nanobody antagonist," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    7. Björn D. M. Bean & Colleen J. Mulvihill & Riddhiman K. Garge & Daniel R. Boutz & Olivier Rousseau & Brendan M. Floyd & William Cheney & Elizabeth C. Gardner & Andrew D. Ellington & Edward M. Marcotte , 2022. "Functional expression of opioid receptors and other human GPCRs in yeast engineered to produce human sterols," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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