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Title: Crystal structure of the[mu]-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 {mu}-opioid receptor ({mu}-OR) in the central nervous system. Here we describe the 2.8 {angstrom} crystal structure of the mouse {mu}-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 {mu}-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.

Authors:
; ; ; ; ; ; ; ; ;  [1];  [2];  [2]
  1. (Michigan-Med)
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NSFOTHERUNIVERSITYNIH
OSTI Identifier:
1043732
Resource Type:
Journal Article
Journal Name:
Nature
Additional Journal Information:
Journal Volume: 485; Journal Issue: 7398
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; BIOLOGY; CENTRAL NERVOUS SYSTEM; CODEINE; CRYSTAL STRUCTURE; DIMERS; MANAGEMENT; MORPHINE; OPIUM; SIDE EFFECTS

Citation Formats

Manglik, Aashish, Kruse, Andrew C., Kobilka, Tong Sun, Thian, Foon Sun, Mathiesen, Jesper M., Sunahara, Roger K., Pardo, Leonardo, Weis, William I., Kobilka, Brian K., Granier, Sébastien, Stanford-MED), and UAB, Spain). Crystal structure of the[mu]-opioid receptor bound to a morphinan antagonist. United States: N. p., 2012. Web. doi:10.1038/nature10954.
Manglik, Aashish, Kruse, Andrew C., Kobilka, Tong Sun, Thian, Foon Sun, Mathiesen, Jesper M., Sunahara, Roger K., Pardo, Leonardo, Weis, William I., Kobilka, Brian K., Granier, Sébastien, Stanford-MED), & UAB, Spain). Crystal structure of the[mu]-opioid receptor bound to a morphinan antagonist. United States. doi:10.1038/nature10954.
Manglik, Aashish, Kruse, Andrew C., Kobilka, Tong Sun, Thian, Foon Sun, Mathiesen, Jesper M., Sunahara, Roger K., Pardo, Leonardo, Weis, William I., Kobilka, Brian K., Granier, Sébastien, Stanford-MED), and UAB, Spain). Wed . "Crystal structure of the[mu]-opioid receptor bound to a morphinan antagonist". United States. doi:10.1038/nature10954.
@article{osti_1043732,
title = {Crystal structure of the[mu]-opioid receptor bound to a morphinan antagonist},
author = {Manglik, Aashish and Kruse, Andrew C. and Kobilka, Tong Sun and Thian, Foon Sun and Mathiesen, Jesper M. and Sunahara, Roger K. and Pardo, Leonardo and Weis, William I. and Kobilka, Brian K. and Granier, Sébastien and Stanford-MED) and UAB, Spain)},
abstractNote = {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 {mu}-opioid receptor ({mu}-OR) in the central nervous system. Here we describe the 2.8 {angstrom} crystal structure of the mouse {mu}-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 {mu}-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.},
doi = {10.1038/nature10954},
journal = {Nature},
number = 7398,
volume = 485,
place = {United States},
year = {2012},
month = {6}
}