Structural insights into µ-opioid receptor activation

Weijiao Huang, Aashish Manglik, A J Venkatakrishnan, Toon Laeremans, Evan N Feinberg, Adrian L Sanborn, Hideaki E Kato, Kathryn E Livingston, Thor S Thorsen, Ralf C Kling, Sébastien Granier, Peter Gmeiner, Stephen M Husbands, John R Traynor, William I Weis, Jan Steyaert, Ron O Dror, Brian K Kobilka

Research output: Contribution to journalArticle

466 Citations (Scopus)
154 Downloads (Pure)

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.

Original languageEnglish
Article number14886
Pages (from-to)315–321
Number of pages7
JournalNature
Volume524
Issue number7565
DOIs
Publication statusPublished - 5 Aug 2015

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