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

• Published in: Nature structural & molecular biology Vol. 22; no. 3; pp. 265 - 268
• Main Authors: Fenalti, Gustavo, Zatsepin, Nadia A, Betti, Cecilia, Giguere, Patrick, Han, Gye Won, Ishchenko, Andrii, Liu, Wei, Guillemyn, Karel, Zhang, Haitao, James, Daniel, Wang, Dingjie, Weierstall, Uwe, Spence, John C H, Boutet, Sébastien, Messerschmidt, Marc, Williams, Garth J, Gati, Cornelius, Yefanov, Oleksandr M, White, Thomas A, Oberthuer, Dominik, Metz, Markus, Yoon, Chun Hong, Barty, Anton, Chapman, Henry N, Basu, Shibom, Coe, Jesse, Conrad, Chelsie E, Fromme, Raimund, Fromme, Petra, Tourwé, Dirk, Schiller, Peter W, Roth, Bryan L, Ballet, Steven, Katritch, Vsevolod, Stevens, Raymond C, Cherezov, Vadim
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2015; Nature Publishing Group
• Subjects: 13/95; 60 APPLIED LIFE SCIENCES; 631/45/611; 631/45/612/194; 631/535/1266; 82/16; 82/29; 82/80; 96/10; 96/33; Analgesics; Binding Sites; Biochemistry; Biological Microscopy; brief-communication; Crystallography, X-Ray; G protein-coupled receptors; Health aspects; HEK293 Cells; Humans; Life Sciences; Membrane Biology; Models, Molecular; Oligopeptides - chemistry; Opioids; Peptides; Protein Structure; Protein Structure, Tertiary; Receptors; Receptors, Opioid, delta - antagonists & inhibitors; Receptors, Opioid, delta - chemistry; Tetrahydroisoquinolines - chemistry; X-ray crystallography; Arizona; Germany; California
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/nsmb.2965

Serial femtosecond crystallography of the human δ-opioid receptor in complex with an endomorphin-derived peptide reveals interactions that are important for understanding the pharmacology of opioid peptides and developing analgesics with reduced side effects. 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-NH 2 (DIPP-NH 2 ) 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.