CONFORMATIONAL-ANALYSIS OF THE ENDOGENOUS MU-OPIOID AGONIST ENDOMORPHIN-1 USING NMR-SPECTROSCOPY AND MOLECULAR MODELING

Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) is a highly selective and potent a gonist of the mu-opioid receptor. To identify structural attributes un ique to this opioid peptide and potential sites of recognition, a conf ormational 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 exist s in the cis- and trans-configuration with respect to the Pro-omega bo nd in approximately 25% and 75% populations, respectively, In DMSO, th e ris-configuration adopts a compact sandwich conformation in which th e Tyr and Trp aromatic rings pack against the proline ring, whereas th e trans-configuration adopts an extended conformation, Although non-ra ndom structure was not observed in water, condensed phase molecular dy namics calculations indicate that tr ans-isomers dominate the populati on in this higher dielectric medium. Structural comparison of the cis- and trans-configurations with morphine and selective mu-peptide ligan ds PL-017 and D-TIPP, as well as the delta-selective peptide ligands T IPP (delta-antagonist, mu-agonist) and DPDPE were also performed and s uggest the tr ans-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, (C) 199 8 Federation of European Biochemical Societies.