Crystal structure of the[mu]-opioid receptor bound to a morphinan antagonist

Journal Article · Wed Jun 27 00:00:00 EDT 2012 · Nature

DOI:https://doi.org/10.1038/nature10954· OSTI ID:1043732

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 ^[1]

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1. Michigan-Med

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.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: NSFOTHERUNIVERSITYNIH
• OSTI ID: 1043732
• Journal Information: Nature, Journal Name: Nature Journal Issue: 7398 Vol. 485
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

60 APPLIED LIFE SCIENCES
BIOLOGY
CENTRAL NERVOUS SYSTEM
CODEINE
CRYSTAL STRUCTURE
DIMERS
MANAGEMENT
MORPHINE
OPIUM
SIDE EFFECTS