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Molecular control of delta-opioid receptor signalling

Academic Article
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Overview

authors

  • Fenalti, G.
  • Giguere, P. M.
  • Katritch, V.
  • Huang, X. P.
  • Thompson, A. A.
  • Cherezov, Vadim
  • Roth, B. L.
  • Stevens, Raymond

publication date

  • February 2014

journal

  • Nature  Journal

abstract

  • Opioids represent widely prescribed and abused medications, although their signal transduction mechanisms are not well understood. Here we present the 1.8?? high-resolution crystal structure of the human ?-opioid receptor (?-OR), revealing the presence and fundamental role of a sodium ion in mediating allosteric control of receptor functional selectivity and constitutive activity. The distinctive ?-OR sodium ion site architecture is centrally located in a polar interaction network in the seven-transmembrane bundle core, with the sodium ion stabilizing a reduced agonist affinity state, and thereby modulating signal transduction. Site-directed mutagenesis and functional studies reveal that changing the allosteric sodium site residue Asn?131 to an alanine or a valine augments constitutive ?-arrestin-mediated signalling. Asp95Ala, Asn310Ala and Asn314Ala mutations transform classical ?-opioid antagonists such as naltrindole into potent ?-arrestin-biased agonists. The data establish the molecular basis for allosteric sodium ion control in opioid signalling, revealing that sodium-coordinating residues act as 'efficacy switches' at a prototypic G-protein-coupled receptor.
  • Opioids represent widely prescribed and abused medications, although their signal transduction mechanisms are not well understood. Here we present the 1.8 Å high-resolution crystal structure of the human δ-opioid receptor (δ-OR), revealing the presence and fundamental role of a sodium ion in mediating allosteric control of receptor functional selectivity and constitutive activity. The distinctive δ-OR sodium ion site architecture is centrally located in a polar interaction network in the seven-transmembrane bundle core, with the sodium ion stabilizing a reduced agonist affinity state, and thereby modulating signal transduction. Site-directed mutagenesis and functional studies reveal that changing the allosteric sodium site residue Asn 131 to an alanine or a valine augments constitutive β-arrestin-mediated signalling. Asp95Ala, Asn310Ala and Asn314Ala mutations transform classical δ-opioid antagonists such as naltrindole into potent β-arrestin-biased agonists. The data establish the molecular basis for allosteric sodium ion control in opioid signalling, revealing that sodium-coordinating residues act as 'efficacy switches' at a prototypic G-protein-coupled receptor.

subject areas

  • Allosteric Regulation
  • Allosteric Site
  • Arrestins
  • Asparagine
  • Crystallography, X-Ray
  • Humans
  • Ligands
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Naltrexone
  • Narcotic Antagonists
  • Receptors, Opioid, delta
  • Signal Transduction
  • Sodium
  • Structure-Activity Relationship
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Identity

PubMed Central ID

  • PMC3931418

International Standard Serial Number (ISSN)

  • 0028-0836

Digital Object Identifier (DOI)

  • 10.1038/nature12944

PubMed ID

  • 24413399
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Additional Document Info

start page

  • 191

end page

  • 196

volume

  • 506

issue

  • 7487

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