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Nature. 2015 Aug 20;524(7565):315-21. doi: 10.1038/nature14886. Epub 2015 Aug 5.

Structural insights into µ-opioid receptor activation.

Author information

1
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA.
2
Department of Computer Science, Stanford University, 318 Campus Drive, Stanford, California 94305, USA.
3
Institute for Computational and Mathematical Engineering, Stanford University, 475 Via Ortega, Stanford, California 94305, USA.
4
Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.
5
Structural Biology Research Center, VIB, Pleinlaan 2, B-1050 Brussels, Belgium.
6
Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, USA.
7
Department of Chemistry and Pharmacy, Friedrich Alexander University, Schuhstrasse 19, 91052 Erlangen, Germany.
8
Institut de Génomique Fonctionnelle, CNRS UMR-5203 INSERM U1191, University of Montpellier, F-34000 Montpellier, France.
9
Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK.
10
Department of Structural Biology, Stanford University School of Medicine, 299 Campus Drive, Stanford, California 94305, USA.

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.

PMID:
26245379
PMCID:
PMC4639397
DOI:
10.1038/nature14886
[Indexed for MEDLINE]
Free PMC Article

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