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Structural insights into µ-opioid receptor activation.

  • Author(s): Huang, Weijiao;
  • Manglik, Aashish;
  • Venkatakrishnan, AJ;
  • Laeremans, Toon;
  • Feinberg, Evan N;
  • Sanborn, Adrian L;
  • Kato, Hideaki E;
  • Livingston, Kathryn E;
  • Thorsen, Thor S;
  • Kling, Ralf C;
  • Granier, Sébastien;
  • Gmeiner, Peter;
  • Husbands, Stephen M;
  • Traynor, John R;
  • Weis, William I;
  • Steyaert, Jan;
  • Dror, Ron O;
  • Kobilka, Brian K
  • et al.
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.

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