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 β 2 -adrenergic receptor (β 2 AR) and the M2 muscarinic receptor. Comparison with active β 2 AR 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.
Original language | English |
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Pages (from-to) | 315-321 |
Number of pages | 7 |
Journal | Nature |
Volume | 524 |
Issue number | 7565 |
Early online date | 5 Aug 2015 |
DOIs | |
Publication status | Published - 20 Aug 2015 |
Keywords
- x-ray crystallography
- G protein-coupled receptor
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Stephen Husbands
- Department of Life Sciences - Professor
- Centre for Therapeutic Innovation
- Addiction and Mental Health Group (AIM)
Person: Research & Teaching