Publication Date:
2015-08-08
Description:
Activation of the mu-opioid receptor (muOR) is responsible for the efficacy of the most effective analgesics. To shed light on the structural basis for muOR activation, here we report a 2.1 A X-ray crystal structure of the murine muOR bound to the morphinan agonist BU72 and a G protein mimetic camelid antibody fragment. The BU72-stabilized changes in the muOR binding pocket are subtle and differ from those observed for agonist-bound structures of the beta2-adrenergic receptor (beta2AR) and the M2 muscarinic receptor. Comparison with active beta2AR reveals a common rearrangement in the packing of three conserved amino acids in the core of the muOR, 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4639397/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4639397/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Weijiao -- Manglik, Aashish -- Venkatakrishnan, A J -- Laeremans, Toon -- Feinberg, Evan N -- Sanborn, Adrian L -- Kato, Hideaki E -- Livingston, Kathryn E -- Thorsen, Thor S -- Kling, Ralf C -- Granier, Sebastien -- Gmeiner, Peter -- Husbands, Stephen M -- Traynor, John R -- Weis, William I -- Steyaert, Jan -- Dror, Ron O -- Kobilka, Brian K -- R01GM083118/GM/NIGMS NIH HHS/ -- R37 DA036246/DA/NIDA NIH HHS/ -- R37DA036246/DA/NIDA NIH HHS/ -- T32 GM008294/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Aug 20;524(7565):315-21. doi: 10.1038/nature14886. Epub 2015 Aug 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA. ; Department of Computer Science, Stanford University, 318 Campus Drive, Stanford, California 94305, USA. ; Institute for Computational and Mathematical Engineering, Stanford University, 475 Via Ortega, Stanford, California 94305, USA. ; Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium. ; Structural Biology Research Center, VIB, Pleinlaan 2, B-1050 Brussels, Belgium. ; Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, USA. ; Department of Chemistry and Pharmacy, Friedrich Alexander University, Schuhstrasse 19, 91052 Erlangen, Germany. ; Institut de Genomique Fonctionnelle, CNRS UMR-5203 INSERM U1191, University of Montpellier, F-34000 Montpellier, France. ; Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK. ; Department of Structural Biology, Stanford University School of Medicine, 299 Campus Drive, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26245379" target="_blank"〉PubMed〈/a〉
Keywords:
Allosteric Regulation
;
Animals
;
Binding Sites
;
Crystallography, X-Ray
;
Heterotrimeric GTP-Binding Proteins/chemistry/metabolism
;
Mice
;
Models, Molecular
;
Molecular Dynamics Simulation
;
Morphinans/chemistry/metabolism/pharmacology
;
Protein Stability/drug effects
;
Protein Structure, Tertiary
;
Pyrroles/chemistry/metabolism/pharmacology
;
Receptor, Muscarinic M2/chemistry
;
Receptors, Adrenergic, beta-2/chemistry
;
Receptors, Opioid, mu/agonists/*chemistry/*metabolism
;
Single-Chain Antibodies/chemistry/pharmacology
;
Structure-Activity Relationship
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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