Conformational analysis of the endogenous μ-opioid agonist endomorphin-1 using NMR spectroscopy and molecular modeling

Brent L. Podlogar, M. Germana Paterlini, David M. Ferguson, Gregory C. Leo, David A. Demeter, Frank K. Brown, Allen B. Reitz

Research output: Contribution to journalArticle

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Abstract

Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) is a highly selective and potent agonist of the μ-opioid receptor. To identify structural attributes unique to this opioid peptide and potential sites of recognition, a conformational analysis has been performed using multidimensional NMR and molecular modeling techniques. The spectroscopic results, derived from experiments in both DMSO and water, indicate that endomorphin-1 exists in the cis- and trans-configuration with respect to the Pro-omega bond in approximately 25% and 75% populations, respectively. In DMSO, the cis-configuration adopts a compact sandwich conformation in which the Tyr and Trp aromatic rings pack against the proline ring, whereas the trans-configuration adopts an extended conformation. Although non-random structure was not observed in water, condensed phase molecular dynamics calculations indicate that trans-isomers dominate the population in this higher dielectric medium. Structural comparison of the cis- and trans-configurations with morphine and selective μ-peptide ligands PL-017 and d-TIPP, as well as the δ-selective peptide ligands TIPP (δ-antagonist, μ-agonist) and DPDPE were also performed and suggest the trans-isomer is likely the bioactive form. A hypothesis is proposed to explain μ- and δ-selectivity based on the presence of spatially distinct selectivity pockets among these ligands. Copyright (C) 1998 Federation of European Biochemical Societies.

Original languageEnglish (US)
Pages (from-to)13-20
Number of pages8
JournalFEBS Letters
Volume439
Issue number1-2
DOIs
StatePublished - Nov 13 1998

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Molecular modeling
Opioid Analgesics
Nuclear magnetic resonance spectroscopy
Magnetic Resonance Spectroscopy
Ligands
Dimethyl Sulfoxide
Isomers
Conformations
D-Penicillamine (2,5)-Enkephalin
Peptides
Opioid Peptides
Water
Opioid Receptors
Molecular Dynamics Simulation
Proline
Morphine
Population
Molecular dynamics
Nuclear magnetic resonance
endomorphin 1

Keywords

  • Conformational analysis
  • Molecular dynamics
  • Multidimensional nuclear magnetic resonance spectroscopy
  • Opioid
  • Peptide structure
  • Structure-activity relationship

Cite this

Conformational analysis of the endogenous μ-opioid agonist endomorphin-1 using NMR spectroscopy and molecular modeling. / Podlogar, Brent L.; Paterlini, M. Germana; Ferguson, David M.; Leo, Gregory C.; Demeter, David A.; Brown, Frank K.; Reitz, Allen B.

In: FEBS Letters, Vol. 439, No. 1-2, 13.11.1998, p. 13-20.

Research output: Contribution to journalArticle

Podlogar, Brent L. ; Paterlini, M. Germana ; Ferguson, David M. ; Leo, Gregory C. ; Demeter, David A. ; Brown, Frank K. ; Reitz, Allen B. / Conformational analysis of the endogenous μ-opioid agonist endomorphin-1 using NMR spectroscopy and molecular modeling. In: FEBS Letters. 1998 ; Vol. 439, No. 1-2. pp. 13-20.
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