Structural insights into [micro]-opioid receptor activation.

• Autores: Weijiao Huang, Aashish Manglik, A. J. Venkatakrishnan, Toon Laeremans, Evan N. Feinberg
• Localización: Nature: International weekly journal of science, ISSN 0028-0836, Vol. 524, Nº 7565, 2015, págs. 315-321
• Idioma: inglés
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• Resumen

  • Activation of the [mu]-opioid receptor ([mu]OR) is responsible for the efficacy of the most effective analgesics. To shed light on the structural basis for [mu]OR activation, here we report a 2.1 A X-ray crystal structure of the murine [mu]OR bound to the morphinan agonist BU72 and a G protein mimetic camelid antibody fragment. The BU72-stabilized changes in the [mu]OR binding pocket are subtle and differ from those observed for agonist-bound structures of the [beta]2-adrenergic receptor ([beta]2AR) and the M2 muscarinic receptor. Comparison with active [beta]2AR reveals a common rearrangement in the packing of three conserved amino acids in the core of the [mu]OR, 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. (C) 2015 Nature Publishing Group