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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Allosteric Regulation
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Animals
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Binding Sites
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Crystallography, X-Ray
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Heterotrimeric GTP-Binding Proteins / chemistry
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Heterotrimeric GTP-Binding Proteins / metabolism
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Mice
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Models, Molecular
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Molecular Dynamics Simulation
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Morphinans / chemistry
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Morphinans / metabolism
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Morphinans / pharmacology
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Protein Stability / drug effects
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Protein Structure, Tertiary
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Pyrroles / chemistry
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Pyrroles / metabolism
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Pyrroles / pharmacology
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Receptor, Muscarinic M2 / chemistry
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Receptors, Adrenergic, beta-2 / chemistry
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Receptors, Opioid, mu / agonists
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Receptors, Opioid, mu / chemistry*
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Receptors, Opioid, mu / metabolism*
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Single-Chain Antibodies / chemistry
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Single-Chain Antibodies / pharmacology
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Structure-Activity Relationship
Substances
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BU72 compound
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Morphinans
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Pyrroles
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Receptor, Muscarinic M2
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Receptors, Adrenergic, beta-2
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Receptors, Opioid, mu
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Single-Chain Antibodies
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Heterotrimeric GTP-Binding Proteins