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

Bi-functional μ- and δ- opioid receptor (OR) ligands are potential therapeutic alternatives to alkaloid opiate analgesics with diminished side effects. We solved the structure of human δ-OR bound to the bi-functional 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. In summary, the observed receptor-peptide interactions are critical to understand the pharmacological profiles of opioid peptides, and to develop improved analgesics.
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [1] ;  [1] ;  [1] ;  [3] ;  [1] ;  [2] ;  [2] ;  [2] ;  [2] ;  [5] ;  [5] ;  [5] ;  [6] ;  [6] ;  [6] ;  [7] more »;  [8] ;  [9] ;  [6] ;  [8] ;  [10] ;  [10] ;  [10] ;  [10] ;  [10] ;  [3] ;  [11] ;  [4] ;  [3] ;  [1] ;  [1] ;  [1] « less
  1. Scripps Research Inst., La Jolla, FL (United States). Dept. of Integrative Structural and Computational Biology
  2. Arizona State Univ., Tempe, AZ (United States). Dept. of Physics
  3. Vrije Univ., Brussels (Belgium). Dept. of Chemistry; Vrije Univ., Brussels (Belgium). Dept. of Bioengineering Sciences
  4. Univ. of North Carolina Chapel Hill Medical School, Chapel Hill, NC (United States). National Inst. of Mental Health; Univ. of North Carolina Chapel Hill Medical School, Chapel Hill, NC (United States). Dept. of Pharmacology; Univ. of North Carolina Chapel Hill Medical School, Chapel Hill, NC (United States). Division of Chemical Biology and Medicinal Chemistry
  5. SLAC National Accelerator Lab., Menlo Park, CA (United States). Linac Coherent Light Source (LCLS)
  6. Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany). Center for Free-Electron Laser Science
  7. Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany). Center for Free-Electron Laser Science; Univ. of Hamburg, Hamburg (Germany). Inst. of Biochemistry and Molecular Biology
  8. Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany). Center for Free-Electron Laser Science; Univ. of Hamburg, Hamburg (Germany). Dept. of Physics
  9. Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany). Center for Free-Electron Laser Science; European X-ray Free-Electron Laser (XFEL), Hamburg (Germany)
  10. Arizona State Univ., Tempe, AZ (United States). Dept. of Chemistry and Biochemistry; Arizona State Univ., Tempe, AZ (United States). Center for Applied Structural Discovery at the Biodesign Inst.
  11. Clinical Research Inst. of Montreal, Montreal, QC (Canada). Lab. of Chemical Biology and Peptide Research
Publication Date:
OSTI Identifier:
1178834
Grant/Contract Number:
U54 GM094618; R01 GM108635; R01 GM108635; R01 GM095583; DA-004443; Y1-CO-1020
Type:
Accepted Manuscript
Journal Name:
Nature Structural & Molecular Biology
Additional Journal Information:
Journal Volume: 22; Journal Issue: 3; Journal ID: ISSN 1545-9993
Publisher:
Nature Publishing Group
Research Org:
Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org:
US National Inst. of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES G protein-coupled receptors; Peptides; X-ray crystallography