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

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