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

著者: Gustavo Fenalti, Nadia A. Zatsepin, Cecilia Betti, Patrick T. Giguere, Gye Won Han, Andrii Ishchenko, Weiwei Liu, Karel Guillemyn, Haitao Zhang, Daniel James, Dingjie Wang, Uwe Weierstall, John C. H. Spence, Sébastien Boutet, M. Messerschmidt, Garth J. Williams, Cornelius Gati, Oleksandr Yefanov, Thomas A. White, D. Oberthüer, Markus Metz, Chun Hong Yoon, Anton Barty, Henry N. Chapman, Shibom Basu, Jesse Coe, Chelsie E. Conrad, Raimund Fromme, Petra Fromme, Dirk Tourwé, Peter W. Schiller, Bryan L. Roth, Steven Ballet, Vsevolod Katritch, Raymond C. Stevens, Vadim Cherezov - Nature Structural & Molecular Biology 2015 被引用: 179

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-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.