Structural insights into μ-opioid receptor activation

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 β2-adrenergic receptor (β2AR) and the M2 muscarinic receptor. Comparison with active β2AR 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. X-ray crystallography and molecular dynamics simulations of the μ-opioid receptor reveal the conformational changes in the extracellular and intracellular domains of this G-protein-coupled receptor that are associated with its activation. The μ-opioid receptor is a G-protein-coupled receptor (GPCR) activated by various analgesics, endogenous endorphins and drugs of abuse such as heroin and opium. Our understanding of the mechanism by which agonist binding leads to recognition, coupling, and activation of a particular G protein subtype is incomplete. In two papers in this issue of Nature, the authors used X-ray crystallography, molecular dynamics simulations, and NMR spectroscopy to probe the structural basis for receptor activation. As well as revealing the conformational changes in the extracellular and intracellular domains of this GPCR associated with receptor activation, these studies help explain why the allosteric coupling between the agonist-binding pocket and the cytoplasmic G-protein-coupling interface of this receptor is relatively weak.