Author
Listed:
- Weijiao Huang
(Stanford University School of Medicine)
- Aashish Manglik
(Stanford University School of Medicine)
- A. J. Venkatakrishnan
(Stanford University School of Medicine
Stanford University
Institute for Computational and Mathematical Engineering, Stanford University)
- Toon Laeremans
(Structural Biology Brussels, Vrije Universiteit Brussel
Structural Biology Research Center, VIB)
- Evan N. Feinberg
(Stanford University School of Medicine
Stanford University
Institute for Computational and Mathematical Engineering, Stanford University)
- Adrian L. Sanborn
(Stanford University School of Medicine
Stanford University
Institute for Computational and Mathematical Engineering, Stanford University)
- 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
Stanford University School of Medicine)
- Jan Steyaert
(Structural Biology Brussels, Vrije Universiteit Brussel
Structural Biology Research Center, VIB)
- Ron O. Dror
(Stanford University School of Medicine
Stanford University
Institute for Computational and Mathematical Engineering, Stanford University)
- Brian K. Kobilka
(Stanford University School of Medicine)
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.
Suggested Citation
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 , 2015.
"Structural insights into µ-opioid receptor activation,"
Nature, Nature, vol. 524(7565), pages 315-321, August.
Handle:
RePEc:nat:nature:v:524:y:2015:i:7565:d:10.1038_nature14886
DOI: 10.1038/nature14886
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