|Title||Structural insights into µ-opioid receptor activation.|
|Publication Type||Journal Article|
|Year of Publication||2015|
|Authors||Huang, W., A. Manglik, A. J. Venkatakrishnan, T. Laeremans, E. N. Feinberg, A. L. Sanborn, H. E. Kato, K. E. Livingston, T. S. Thorsen, R. C. Kling, S. Granier, P. Gmeiner, S. M. Husbands, J. R. Traynor, W. I. Weis, J. Steyaert, R. O. Dror, and B. K. Kobilka|
|Date Published||2015 Aug 20|
|Keywords||Allosteric Regulation, Animals, Binding Sites, Crystallography, X-Ray, Heterotrimeric GTP-Binding Proteins, Mice, Models, Molecular, Molecular Dynamics Simulation, Morphinans, Protein Stability, Protein Structure, Tertiary, Pyrroles, Receptor, Muscarinic M2, Receptors, Adrenergic, beta-2, Receptors, Opioid, mu, Single-Chain Antibodies, Structure-Activity Relationship|
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.
|PubMed Central ID||PMC4639397|
|Grant List||R01GM083118 / GM / NIGMS NIH HHS / United States |
T32 GM008294 / GM / NIGMS NIH HHS / United States
R01 GM083118 / GM / NIGMS NIH HHS / United States
R37DA036246 / DA / NIDA NIH HHS / United States
R37 DA036246 / DA / NIDA NIH HHS / United States
Structural insights into µ-opioid receptor activation.