IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v485y2012i7398d10.1038_nature10954.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/nature10954
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.
    File URL: https://libkey.io/10.1038/nature10954?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    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. 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.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:485:y:2012:i:7398:d:10.1038_nature10954. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.