Conformational analysis of the endogenous mu-opioid agonist endomorphin-1 using NMR spectroscopy and molecular modeling.
FEBS Lett
; 439(1-2): 13-20, 1998 Nov 13.
Article
em En
| MEDLINE
| ID: mdl-9849868
ABSTRACT
Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) is a highly selective and potent agonist of the mu-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 mu-peptide ligands PL-017 and D-TIPP, as well as the delta-selective peptide ligands TIPP (delta-antagonist, mu-agonist) and DPDPE were also performed and suggest the trans-isomer is likely the bioactive form. A hypothesis is proposed to explain mu- and delta-selectivity based on the presence of spatially distinct selectivity pockets among these ligands.
Buscar no Google
Base de dados:
MEDLINE
Assunto principal:
Oligopeptídeos
/
Receptores Opioides mu
Idioma:
En
Ano de publicação:
1998
Tipo de documento:
Article