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 and Brian K. Kobilka ()
Additional contact information
Weijiao Huang: Stanford University School of Medicine
Aashish Manglik: Stanford University School of Medicine
A. J. Venkatakrishnan: Stanford University School of Medicine
Toon Laeremans: Structural Biology Brussels, Vrije Universiteit Brussel
Evan N. Feinberg: Stanford University School of Medicine
Adrian L. Sanborn: Stanford University School of Medicine
Hideaki E. Kato: Stanford University School of Medicine
Kathryn E. Livingston: University of Michigan
Thor S. Thorsen: Stanford University School of Medicine
Ralf C. Kling: Friedrich Alexander University
Sébastien Granier: Institut de Génomique Fonctionnelle, CNRS UMR-5203 INSERM U1191, University of Montpellier
Peter Gmeiner: Friedrich Alexander University
Stephen M. Husbands: University of Bath
John R. Traynor: University of Michigan
William I. Weis: Stanford University School of Medicine
Jan Steyaert: Structural Biology Brussels, Vrije Universiteit Brussel
Ron O. Dror: Stanford University School of Medicine
Brian K. Kobilka: Stanford University School of Medicine

Nature, 2015, vol. 524, issue 7565, 315-321

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature14886

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