DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: 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
 [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]; ORCiD logo [10];  [10];  [10];  [10];  [3];  [11];  [4];  [3];  [1];  [1]; ORCiD logo [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

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:
National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
U54 GM094618; R01 GM108635; R01 GM095583; DA-004443; Y1-CO-1020
OSTI ID:
1178834
Journal Information:
Nature Structural & Molecular Biology, Vol. 22, Issue 3; ISSN 1545-9993
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 130 works
Citation information provided by
Web of Science

References (53)

Cheetah : software for high-throughput reduction and analysis of serial femtosecond X-ray diffraction data journal May 2014
CrystFEL : a software suite for snapshot serial crystallography journal March 2012
Synthesis, Modeling, and Pharmacological Evaluation of UMB 425, a Mixed μ Agonist/δ Antagonist Opioid Analgesic with Reduced Tolerance Liabilities journal June 2013
Crystal structure of the µ-opioid receptor bound to a morphinan antagonist journal March 2012
Refinement of Macromolecular Structures by the Maximum-Likelihood Method journal May 1997
Lipidic cubic phase injector facilitates membrane protein serial femtosecond crystallography journal February 2014
Detection of beta 2-adrenergic receptor dimerization in living cells using bioluminescence resonance energy transfer (BRET) journal March 2000
Features and development of Coot journal March 2010
Opioids and their receptors: Are we there yet? journal January 2014
TIPP[.psi.]: a highly potent and stable pseudopeptide .delta. opioid receptor antagonist with extraordinary .delta. selectivity journal October 1993
The Opioid μ Agonist/δ Antagonist DIPP-NH2[Ψ] Produces a Potent Analgesic Effect, No Physical Dependence, and Less Tolerance than Morphine in Rats journal August 1999
Structural studies of [2′,6′-dimethyl-l-tyrosine1]endomorphin-2 analogues: enhanced activity and cis orientation of the Dmt-Pro amide bond journal May 2003
Conformationally constrained opioid ligands: The Dmt-Aba and Dmt-Aia versus Dmt-Tic scaffold journal January 2009
Structure of the human κ-opioid receptor in complex with JDTic journal March 2012
PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
Bi- or multifunctional opioid peptide drugs journal April 2010
Structure of the agonist-bound neurotensin receptor journal October 2012
Structural Basis for Allosteric Regulation of GPCRs by Sodium Ions journal July 2012
Molecular control of δ-opioid receptor signalling journal January 2014
Structure of the δ-opioid receptor bound to naltrindole journal May 2012
Preparation of microcrystals in lipidic cubic phase for serial femtosecond crystallography journal August 2014
Crystallizing membrane proteins using lipidic mesophases journal April 2009
Dmt and opioid peptides: A potent alliance journal January 2003
[20] Processing of X-ray diffraction data collected in oscillation mode book January 1997
The genetic design of signaling cascades to record receptor activation journal December 2007
Influence of sample pH on the conformational backbone dynamics of a pseudotripeptide (H-Tyr-Tic?[CH2-NH] Phe-OH) incorporating a reduced peptide bond: An NMR investigation journal December 1995
Differential stereochemical requirements of mu vs. delta opioid receptors for ligand binding and signal transduction: development of a class of potent and highly delta-selective peptide antagonists. journal December 1992
Serial Femtosecond Crystallography of G Protein-Coupled Receptors journal December 2013
Phaser crystallographic software journal July 2007
Subtleties of Structure-Agonist Versus Antagonist Relationships of Opioid Peptides and Peptidomimetics journal January 1999
PARP1 exhibits enhanced association and catalytic efficiency with γH2A.X-nucleosome journal December 2019
Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation journal February 2021
Molecular control of δ-opioid receptor signalling text January 2014
PHENIX: a comprehensive Python-based system for macromolecular structure solution. text January 2010
Influence of sample pH on the conformational backbone dynamics of a pseudotripeptide (H-Tyr-Tic?[CH2-NH] Phe-OH) incorporating a reduced peptide bond: An NMR investigation journal December 1995
Conformationally constrained opioid ligands: The Dmt-Aba and Dmt-Aia versus Dmt-Tic scaffold journal January 2009
Bi- or multifunctional opioid peptide drugs journal April 2010
Opioids and their receptors: Are we there yet? journal January 2014
Redesign of a Four-helix Bundle Protein by Phage Display Coupled with Proteolysis and Structural Characterization by NMR and X-ray Crystallography journal October 2002
Synthesis, Modeling, and Pharmacological Evaluation of UMB 425, a Mixed μ Agonist/δ Antagonist Opioid Analgesic with Reduced Tolerance Liabilities journal June 2013
TIPP[.psi.]: a highly potent and stable pseudopeptide .delta. opioid receptor antagonist with extraordinary .delta. selectivity journal October 1993
Structure of the human κ-opioid receptor in complex with JDTic journal March 2012
Structure of the δ-opioid receptor bound to naltrindole journal May 2012
Structure of the agonist-bound neurotensin receptor journal October 2012
Lipidic cubic phase injector facilitates membrane protein serial femtosecond crystallography journal February 2014
Crystallizing membrane proteins using lipidic mesophases journal April 2009
Preparation of microcrystals in lipidic cubic phase for serial femtosecond crystallography journal August 2014
The genetic design of signaling cascades to record receptor activation journal December 2007
Differential stereochemical requirements of mu vs. delta opioid receptors for ligand binding and signal transduction: development of a class of potent and highly delta-selective peptide antagonists. journal December 1992
Detection of β 2 -adrenergic receptor dimerization in living cells using bioluminescence resonance energy transfer (BRET) journal March 2000
Structural Basis for Allosteric Regulation of GPCRs by Sodium Ions journal July 2012
Serial Femtosecond Crystallography of G Protein-Coupled Receptors journal December 2013
PHENIX: a comprehensive Python-based system for macromolecular structure solution. text January 2010

Cited By (47)

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
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
Time-resolved structural studies with serial crystallography: A new light on retinal proteins journal June 2015
Targeting delta opioid receptors for pain treatment: drugs in phase I and II clinical development journal December 2016
An outlook on using serial femtosecond crystallography in drug discovery journal May 2019
X-ray free-electron laser: opportunities for drug discovery journal July 2018
In meso in situ serial X-ray crystallography of soluble and membrane proteins journal May 2015
DatView : a graphical user interface for visualizing and querying large data sets in serial femtosecond crystallography journal October 2019
SPIND : a reference-based auto-indexing algorithm for sparse serial crystallography data journal January 2019
Toward G protein-coupled receptor structure-based drug design using X-ray lasers journal October 2019
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
Elucidating the active δ-opioid receptor crystal structure with peptide and small-molecule agonists journal November 2019
Lipidic cubic phase injector is a viable crystal delivery system for time-resolved serial crystallography text January 2016
Short-wavelength free-electron laser sources and science: a review text January 2017
The Effects of Opioids on HIV Neuropathogenesis journal October 2019
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
Short-wavelength free-electron laser sources and science: a review journal October 2017
Serial femtosecond crystallography datasets from G protein-coupled receptors text January 2016
A New DREADD Facilitates the Multiplexed Chemogenetic Interrogation of Behavior journal May 2015
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

Figures / Tables (2)