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 journalArticlepeer-review

80 Scopus citations

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

Bibliographical note

Funding Information:
We thank Dr. Kenway Hoey and Ms. Anita Everson for the synthesis of the endomorphin-1 required for these studies. DMF acknowledges support from NIDA/NIH. Supporting information available: ROESY and NOESY spectra are available. In addition, all aspects of the molecular dynamics simulations and structures are available upon request.

Keywords

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

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