Crystal structure of the µ-opioid receptor bound to a morphinan antagonist
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Open Access
- 21 March 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 485 (7398), 321-326
- https://doi.org/10.1038/nature10954
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.Keywords
This publication has 46 references indexed in Scilit:
- Structure and dynamics of the M3 muscarinic acetylcholine receptorNature, 2012
- Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonistNature, 2012
- Emerging paradigms of β-arrestin-dependent seven transmembrane receptor signalingTrends in Biochemical Sciences, 2011
- Crystal structure of the β2 adrenergic receptor–Gs protein complexNature, 2011
- Differential Response to Morphine of the Oligomeric State of μ-Opioid in the Presence of δ-Opioid ReceptorsBiochemistry, 2011
- Making Structural Sense of Dimerization Interfaces of Delta Opioid Receptor HomodimersBiochemistry, 2011
- Morphine-like Opiates Selectively Antagonize Receptor-Arrestin InteractionsPublished by Elsevier BV ,2010
- Ligand-regulated oligomerization of β2-adrenoceptors in a model lipid bilayerThe EMBO Journal, 2009
- Crystallizing membrane proteins using lipidic mesophasesNature Protocols, 2009
- [20] Processing of X-ray diffraction data collected in oscillation modeMethods in Enzymology, 1997