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Molecular control of δ-opioid receptor signalling

Author

Listed:
  • Gustavo Fenalti

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Patrick M. Giguere

    (University of North Carolina Chapel Hill Medical School)

  • Vsevolod Katritch

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Xi-Ping Huang

    (University of North Carolina Chapel Hill Medical School)

  • Aaron A. Thompson

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Vadim Cherezov

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Bryan L. Roth

    (University of North Carolina Chapel Hill Medical School)

  • Raymond C. Stevens

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

Abstract

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.

Suggested Citation

  • Gustavo Fenalti & Patrick M. Giguere & Vsevolod Katritch & Xi-Ping Huang & Aaron A. Thompson & Vadim Cherezov & Bryan L. Roth & Raymond C. Stevens, 2014. "Molecular control of δ-opioid receptor signalling," Nature, Nature, vol. 506(7487), pages 191-196, February.
    • Handle: RePEc:nat:nature:v:506:y:2014:i:7487:d:10.1038_nature12944
    DOI: 10.1038/nature12944
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    Cited by:

    1. Shun Kaneko & Shunsuke Imai & Tomomi Uchikubo-Kamo & Tamao Hisano & Nobuaki Asao & Mikako Shirouzu & Ichio Shimada, 2024. "Structural and dynamic insights into the activation of the μ-opioid receptor by an allosteric modulator," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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