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Structure of the δ-opioid receptor bound to naltrindole


The opioid receptor family comprises three members, the µ-, δ- and κ-opioid receptors, which respond to classical opioid alkaloids such as morphine and heroin as well as to endogenous peptide ligands like endorphins. They belong to the G-protein-coupled receptor (GPCR) superfamily, and are excellent therapeutic targets for pain control. The δ-opioid receptor (δ-OR) has a role in analgesia, as well as in other neurological functions that remain poorly understood1. The structures of the µ-OR and κ-OR have recently been solved2,3. Here we report the crystal structure of the mouse δ-OR, bound to the subtype-selective antagonist naltrindole. Together with the structures of the µ-OR and κ-OR, the δ-OR structure provides insights into conserved elements of opioid ligand recognition while also revealing structural features associated with ligand-subtype selectivity. The binding pocket of opioid receptors can be divided into two distinct regions. Whereas the lower part of this pocket is highly conserved among opioid receptors, the upper part contains divergent residues that confer subtype selectivity. This provides a structural explanation and validation for the ‘message–address’ model of opioid receptor pharmacology4,5, in which distinct ‘message’ (efficacy) and ‘address’ (selectivity) determinants are contained within a single ligand. Comparison of the address region of the δ-OR with other GPCRs reveals that this structural organization may be a more general phenomenon, extending to other GPCR families as well.

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Figure 1: Overall structure of the δ-OR.
Figure 2: Ligand-binding site of the δ-OR.
Figure 3: A conserved opioid ligand recognition mode.
Figure 4: The message–address hypothesis is reflected in opioid receptor structure.

Accession codes

Primary accessions

Protein Data Bank

Data deposits

Coordinates and structure factors for δ-OR–T4L are deposited in the Protein Data Bank under accession code 4EJ4.


  1. Pradhan, A. A., Befort, K., Nozaki, C., Gaveriaux-Ruff, C. & Kieffer, B. L. The delta opioid receptor: an evolving target for the treatment of brain disorders. Trends Pharmacol. Sci. 32, 581–590 (2011)

    Article  CAS  Google Scholar 

  2. Manglik, A. et al. Crystal structure of the μ-opioid receptor bound to a morphinan antagonist. Nature (this issue)

  3. Wu, H. et al. Structure of the human κ-opioid receptor in complex with JDTic. Nature (this issue)

  4. Chavkin, C. & Goldstein, A. Specific receptor for the opioid peptide dynorphin: structure–activity relationships. Proc. Natl Acad. Sci. USA 78, 6543–6547 (1981)

    Article  ADS  CAS  Google Scholar 

  5. Lipkowski, A. W., Tam, S. W. & Portoghese, P. S. Peptides as receptor selectivity modulators of opiate pharmacophores. J. Med. Chem. 29, 1222–1225 (1986)

    Article  CAS  Google Scholar 

  6. Satoh, M. & Minami, M. Molecular pharmacology of the opioid receptors. Pharmacol. Ther. 68, 343–364 (1995)

    Article  CAS  Google Scholar 

  7. Mollereau, C. et al. ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization. FEBS Lett. 341, 33–38 (1994)

    Article  CAS  Google Scholar 

  8. Cox, B. M. et al. Opioid Receptors: Introduction (2009)

  9. Portoghese, P. S., Sultana, M., Nagase, H. & Takemori, A. E. Application of the message-address concept in the design of highly potent and selective non-peptide δ opioid receptor antagonists. J. Med. Chem. 31, 281–282 (1988)

    Article  CAS  Google Scholar 

  10. Warne, T. et al. Structure of a β1-adrenergic G-protein-coupled receptor. Nature 454, 486–491 (2008)

    Article  ADS  CAS  Google Scholar 

  11. George, S. R. et al. Oligomerization of μ- and δ-opioid receptors. Generation of novel functional properties. J. Biol. Chem. 275, 26128–26135 (2000)

    Article  CAS  Google Scholar 

  12. Portoghese, P. S., Larson, D. L., Sayre, L. M., Fries, D. S. & Takemori, A. E. A novel opioid receptor site directed alkylating agent with irreversible narcotic antagonistic and reversible agonistic activities. J. Med. Chem. 23, 233–234 (1980)

    Article  CAS  Google Scholar 

  13. Bonner, G., Meng, F. & Akil, H. Selectivity of μ-opioid receptor determined by interfacial residues near third extracellular loop. Eur. J. Pharmacol. 403, 37–44 (2000)

    Article  CAS  Google Scholar 

  14. Meng, F. et al. Creating a functional opioid alkaloid binding site in the orphanin FQ receptor through site-directed mutagenesis. Mol. Pharmacol. 53, 772–777 (1998)

    Article  CAS  Google Scholar 

  15. Eguchi, M. Recent advances in selective opioid receptor agonists and antagonists. Med. Res. Rev. 24, 182–212 (2004)

    Article  CAS  Google Scholar 

  16. Haga, K. et al. Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist. Nature 482, 547–551 (2011)

    Article  ADS  Google Scholar 

  17. Valant, C. et al. A novel mechanism of G protein-coupled receptor functional selectivity. Muscarinic partial agonist McN-A-343 as a bitopic orthosteric/allosteric ligand. J. Biol. Chem. 283, 29312–29321 (2008)

    Article  CAS  Google Scholar 

  18. Metzger, T. G., Paterlini, M. G., Ferguson, D. M. & Portoghese, P. S. Investigation of the selectivity of oxymorphone- and naltrexone-derived ligands via site-directed mutagenesis of opioid receptors: exploring the “address” recognition locus. J. Med. Chem. 44, 857–862 (2001)

    Article  CAS  Google Scholar 

  19. Xue, J. C. et al. Differential binding domains of peptide and non-peptide ligands in the cloned rat κ opioid receptor. J. Biol. Chem. 269, 30195–30199 (1994)

    CAS  PubMed  Google Scholar 

  20. Pepin, M. C., Yue, S. Y., Roberts, E., Wahlestedt, C. & Walker, P. Novel “restoration of function” mutagenesis strategy to identify amino acids of the δ-opioid receptor involved in ligand binding. J. Biol. Chem. 272, 9260–9267 (1997)

    Article  CAS  Google Scholar 

  21. Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307–326 (1997)

    Article  CAS  Google Scholar 

  22. McCoy, A. J. et al. Phaser crystallographic software. J. Appl. Cryst. 40, 658–674 (2007)

    Article  CAS  Google Scholar 

  23. Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D 60, 2126–2132 (2004)

    Article  Google Scholar 

  24. Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D 66, 213–221 (2010)

    Article  CAS  Google Scholar 

  25. Chen, V. B. et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D 66, 12–21 (2010)

    Article  CAS  Google Scholar 

  26. The. PyMOL Molecular Graphics System v. (Schrödinger, LLC, 2012).

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We thank R. Sunahara for helpful suggestions on opioid receptor pharmacology and biochemistry. We acknowledge support from INSERM (S.G.), the Stanford Medical Scientist Training Program (A.M.), the National Science Foundation (A.C.K.), National Institutes of Health grants NS028471 (B.K.K.) and DA031418 (B.K.K.), and from the Mathers Foundation (B.K.K. and W.I.W.).

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Authors and Affiliations



A.M., A.C.K. and S.G. designed experiments, performed research and analysed data. T.S.K. and F.S.T. expressed and purified receptor. W.I.W. supervised diffraction data analysis and model refinement. A.M., A.C.K., S.G. and B.K.K. prepared the manuscript. S.G. and B.K.K. supervised the research.

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Correspondence to Sébastien Granier or Brian K. Kobilka.

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The authors declare no competing financial interests.

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Granier, S., Manglik, A., Kruse, A. et al. Structure of the δ-opioid receptor bound to naltrindole. Nature 485, 400–404 (2012).

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