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Structural insights into [micro]-opioid receptor activation
Ist Teil von
Nature (London), 2015-08, Vol.524 (7565), p.315
Ort / Verlag
London: Nature Publishing Group
Erscheinungsjahr
2015
Quelle
EBSCOhost Psychology and Behavioral Sciences Collection
Beschreibungen/Notizen
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 Å 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].sub.2-adrenergic receptor ([beta].sub.2AR) and the M2 muscarinic receptor. Comparison with active [beta].sub.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.