title: Crystal structure of the µ-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 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.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Aashish
authors.initials: A
authors.lastname: Manglik
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Kruse
authors.forename: Tong Sun
authors.initials: TS
authors.lastname: Kobilka
authors.forename: Foon Sun
authors.initials: FS
authors.lastname: Thian
authors.forename: Jesper M
authors.initials: JM
authors.lastname: Mathiesen
authors.forename: Roger K
authors.initials: RK
authors.lastname: Sunahara
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pardo
authors.forename: William I
authors.initials: WI
authors.lastname: Weis
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kobilka
authors.forename: Sébastien
authors.initials: S
authors.lastname: Granier
mesh_terms: D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D009019:Morphinans / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D055503:Protein Multimerization; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D012997:Solvents / Q000737:chemistry
chemical_list: D008024:Ligands; D009019:Morphinans; D017450:Receptors, Opioid, mu; D012997:Solvents