title: Structural insights into µ-opioid receptor activation.
abstract: Activation of the μ-opioid receptor (μOR) is responsible for the efficacy of the most effective analgesics. To shed light on the structural basis for μOR activation, here we report a 2.1 Å X-ray crystal structure of the murine μOR bound to the morphinan agonist BU72 and a G protein mimetic camelid antibody fragment. The BU72-stabilized changes in the μOR binding pocket are subtle and differ from those observed for agonist-bound structures of the β2-adrenergic receptor (β2AR) and the M2 muscarinic receptor. Comparison with active β2AR reveals a common rearrangement in the packing of three conserved amino acids in the core of the μOR, and molecular dynamics simulations illustrate how the ligand-binding pocket is conformationally linked to this conserved triad. Additionally, an extensive polar network between the ligand-binding pocket and the cytoplasmic domains appears to play a similar role in signal propagation for all three G-protein-coupled receptors.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA.
authors.forename: Weijiao
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA.
authors.forename: Aashish
authors.initials: A
authors.lastname: Manglik
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA.|Department of Computer Science, Stanford University, 318 Campus Drive, Stanford, California 94305, USA.|Institute for Computational and Mathematical Engineering, Stanford University, 475 Via Ortega, Stanford, California 94305, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Venkatakrishnan
authors.affiliation: Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.|Structural Biology Research Center, VIB, Pleinlaan 2, B-1050 Brussels, Belgium.
authors.forename: Toon
authors.initials: T
authors.lastname: Laeremans
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA.|Department of Computer Science, Stanford University, 318 Campus Drive, Stanford, California 94305, USA.|Institute for Computational and Mathematical Engineering, Stanford University, 475 Via Ortega, Stanford, California 94305, USA.
authors.forename: Evan N
authors.initials: EN
authors.lastname: Feinberg
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA.|Department of Computer Science, Stanford University, 318 Campus Drive, Stanford, California 94305, USA.|Institute for Computational and Mathematical Engineering, Stanford University, 475 Via Ortega, Stanford, California 94305, USA.
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Sanborn
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA.
authors.forename: Hideaki E
authors.initials: HE
authors.lastname: Kato
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Livingston
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA.
authors.forename: Thor S
authors.initials: TS
authors.lastname: Thorsen
authors.affiliation: Department of Chemistry and Pharmacy, Friedrich Alexander University, Schuhstrasse 19, 91052 Erlangen, Germany.
authors.forename: Ralf C
authors.initials: RC
authors.lastname: Kling
authors.affiliation: Institut de Génomique Fonctionnelle, CNRS UMR-5203 INSERM U1191, University of Montpellier, F-34000 Montpellier, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Granier
authors.affiliation: Department of Chemistry and Pharmacy, Friedrich Alexander University, Schuhstrasse 19, 91052 Erlangen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Husbands
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Traynor
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA.|Department of Structural Biology, Stanford University School of Medicine, 299 Campus Drive, Stanford, California 94305, USA.
authors.forename: William I
authors.initials: WI
authors.lastname: Weis
authors.affiliation: Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.|Structural Biology Research Center, VIB, Pleinlaan 2, B-1050 Brussels, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Steyaert
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA.|Department of Computer Science, Stanford University, 318 Campus Drive, Stanford, California 94305, USA.|Institute for Computational and Mathematical Engineering, Stanford University, 475 Via Ortega, Stanford, California 94305, USA.
authors.forename: Ron O
authors.initials: RO
authors.lastname: Dror
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kobilka
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D020962:Heterotrimeric GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009019:Morphinans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D043585:Receptor, Muscarinic M2 / Q000737:chemistry; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism*; D057127:Single-Chain Antibodies / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C496287:BU72 compound; D009019:Morphinans; D011758:Pyrroles; D043585:Receptor, Muscarinic M2; D018343:Receptors, Adrenergic, beta-2; D017450:Receptors, Opioid, mu; D057127:Single-Chain Antibodies; D020962:Heterotrimeric GTP-Binding Proteins