Journal
NATURE
Volume 524, Issue 7565, Pages 315-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature14886
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Funding
- Stanford Medical Scientist Training Program
- American Heart Association
- National Institutes of Health [R37DA036246, R01GM083118]
- Terman Faculty Fellowship
- Eli Lilly and Company through the Lilly Research Program
- Mathers Foundation
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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 angstrom 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(2)AR) and the M2 muscarinic receptor. Comparison with active beta(2)AR 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.
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