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

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 () and Sébastien Granier ()
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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
Brian K. Kobilka: Stanford University School of Medicine
Sébastien Granier: Stanford University School of Medicine

Nature, 2012, vol. 485, issue 7398, 321-326

Abstract: 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.

Date: 2012
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DOI: 10.1038/nature10954

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