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

Journal Article · · Nature Structural & Molecular Biology
DOI:https://doi.org/10.1038/nsmb.2965· OSTI ID:1178834
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  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
+ Show Author Affiliations

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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)
OSTI ID:
1178834
Alternate ID(s):
OSTI ID: 2530157
Journal Information:
Nature Structural & Molecular Biology, Journal Name: Nature Structural & Molecular Biology Journal Issue: 3 Vol. 22; ISSN 1545-9993
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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G Protein-Coupled Receptors: Dynamic Machines for Signaling Pain and Itch journal November 2015
Toward a Universal μ-Agonist Template for Template-Based Alignment Modeling of Opioid Ligands journal October 2019
Structure of the µ-opioid receptor–Gi protein complex journal June 2018
On resin click-chemistry-mediated synthesis of novel enkephalin analogues with potent anti-nociceptive activity journal April 2019
Serial femtosecond crystallography datasets from G protein-coupled receptors journal August 2016
Possibilities for serial femtosecond crystallography sample delivery at future light sourcesa) journal May 2015
Serial femtosecond X-ray diffraction of enveloped virus microcrystals journal July 2015
Pharmacology of W-18 and W-15 posted_content July 2016
Understanding Peptide Binding in Class A G Protein-Coupled Receptors journal July 2019
Elucidating the active δ-opioid receptor crystal structure with peptide and small-molecule agonists journal November 2019
Single Amino Acid Variation Underlies Species-Specific Sensitivity to Amphibian Skin-Derived Opioid-like Peptides text January 2015
In Silico Studies Targeting G-protein Coupled Receptors for Drug Research Against Parkinson’s Disease journal June 2018
The Effects of Opioids on HIV Neuropathogenesis journal October 2019
G Protein-Coupled Receptors (GPCRs) in Alzheimer’s Disease: A Focus on BACE1 Related GPCRs journal March 2016
Opportunities and Challenges for In Silico Drug Discovery at Delta Opioid Receptors journal July 2022
Preparation and Delivery of Protein Microcrystals in Lipidic Cubic Phase for Serial Femtosecond Crystallography journal September 2016
An Ultra-Compact X-Ray Free-Electron Laser text January 2020
Atomic resolution structure determination by the cryo-EM method MicroED: Atomic Resolution Structure Determination journal August 2016
New approaches towards the understanding of integral membrane proteins: A structural perspective on G protein-coupled receptors: Structural Perspective on G Protein-Coupled Receptors journal June 2017
Structures of Non-rhodopsin GPCRs Elucidated Through X-Ray Crystallography book January 2017
Crystallization of Membrane Proteins: An Overview book January 2017
A benchmark study of loop modeling methods applied to G protein-coupled receptors journal May 2019
Structure-based discovery of opioid analgesics with reduced side effects journal August 2016
Hitchhiking on the heptahelical highway: structure and function of 7TM receptor complexes journal April 2016
X-ray free electron laser: opportunities for drug discovery journal November 2017
Time-resolved structural studies with serial crystallography: A new light on retinal proteins journal June 2015
Non-cryogenic structure of a chloride pump provides crucial clues to temperature-dependent channel transport efficiency journal November 2018
Targeting delta opioid receptors for pain treatment: drugs in phase I and II clinical development journal December 2016
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Toward G protein-coupled receptor structure-based drug design using X-ray lasers journal October 2019
In meso in situ serial X-ray crystallography of soluble and membrane proteins at cryogenic temperatures journal January 2016
Insights into the function of opioid receptors from molecular dynamics simulations of available crystal structures journal April 2017
Molecular Pharmacology of δ -Opioid Receptors journal May 2016
Structure-based discovery of opioid analgesics with reduced side effects text January 2016
Time-resolved structural studies with serial crystallography: A new light on retinal proteins text January 2015
Lipidic cubic phase injector is a viable crystal delivery system for time-resolved serial crystallography text January 2016
Serial femtosecond crystallography datasets from G protein-coupled receptors text January 2016
Short-wavelength free-electron laser sources and science: a review text January 2017
Lipidic cubic phase injector is a viable crystal delivery system for time-resolved serial crystallography text January 2016

Figures / Tables (2)

Figure 1(p. 12)figure Figure 1
Figure 2(p. 13)figure Figure 2

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Related Subjects

60 APPLIED LIFE SCIENCES
G protein-coupled receptors
Peptides
X-ray crystallography