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.