Structural basis for bifunctional peptide recognition at human δ-opioid receptor

Nat Struct Mol Biol. 2015 Mar;22(3):265-8. doi: 10.1038/nsmb.2965. Epub 2015 Feb 16.


Bifunctional μ- and δ-opioid receptor (OR) ligands are potential therapeutic alternatives, with diminished side effects, to alkaloid opiate analgesics. We solved the structure of human δ-OR bound to the bifunctional δ-OR antagonist and μ-OR agonist tetrapeptide H-Dmt-Tic-Phe-Phe-NH2 (DIPP-NH2) by serial femtosecond crystallography, revealing a cis-peptide bond between H-Dmt and Tic. The observed receptor-peptide interactions are critical for understanding of the pharmacological profiles of opioid peptides and for development of improved analgesics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Oligopeptides / chemistry
  • Protein Structure, Tertiary
  • Receptors, Opioid, delta / antagonists & inhibitors
  • Receptors, Opioid, delta / chemistry*
  • Tetrahydroisoquinolines / chemistry


  • 2',6'-dimethyltyrosyl-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-phenylalanyl-phenylalaninamide
  • Oligopeptides
  • Receptors, Opioid, delta
  • Tetrahydroisoquinolines

Associated data

  • PDB/4RWA
  • PDB/4RWD