Structural insights into µ-opioid receptor activation.

TitleStructural insights into µ-opioid receptor activation.
Publication TypeJournal Article
Year of Publication2015
AuthorsHuang, 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 Published2015 Aug 20
KeywordsAllosteric 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.

Alternate JournalNature
PubMed ID26245379
PubMed Central IDPMC4639397
Grant ListR01GM083118 / 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
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