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

By A. Manglik, A. Kruse, T. S. Kobilka, Foon Sun Thian, J. M. Mathiesen, R. Sunahara, L. Pardo, William I. Weis, Brian K. Kobilka, S. Granier. Nature, 2012

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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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7537b545fde090f4622224bb6558a29ee719ffab

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Citations in the corpus

GPCR Network: a large-scale collaboration on GPCR structure and function (2012, background): “32) , mouse μ-type opioid receptor 33 , mouse δ-type opioid receptor 34 and rat neurotensin receptor 35 .”
A G Protein-Biased Ligand at the μ-Opioid Receptor Is Potently Analgesic with Reduced Gastrointestinal and Respiratory Dysfunction Compared with Morphine (2013, background): “In addition, the recently published MOR crystal structure may permit investigation of how biased and unbiased ligands may engage different conformations of the MOR to support selective coupling to G proteins versus b-arrestins (Manglik et al., 2012).”
Computational design of environmental sensors for the potent opioid fentanyl (2017, background): “Fentanyl is likely to make a direct salt bridge with MOR via its tertiary amine and a con- served aspartate in the third transmembrane helix of the receptor (Manglik et al., 2016; Manglik et al., 2012).”
Structure-based drug screening for G-protein-coupled receptors. (2012, background): “Since the initial crystal structures of the β2AR[11] and the β1AR[12], the number of published GPCRs which have yielded to crystallography has grown to ten and includes the adenosine A2A receptor[13], the D3 dopamine receptor[14], the CXCR4 receptor [15], the histamine H1 receptor, [16], the sphingo”
Regulation of µ-Opioid Receptors: Desensitization, Phosphorylation, Internalization, and Tolerance (2013, background): “X-ray crystal structures of the MOR, DOR, and KOR have been recently reported (Granier et al., 2012; Manglik et al., 2012; Wu et al., 2012), as was a structure of the orphanin FQ receptor (Thompson et al.”
Natural Products for Drug Discovery in the 21st Century: Innovations for Novel Drug Discovery (2018, background): “Some of these natural products include opium and morphine [52,53].”