title: Conformational analysis of the endogenous mu-opioid agonist endomorphin-1 using NMR spectroscopy and molecular modeling.
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.
authors.affiliation: Department of Medicinal Chemistry, The R.W. Johnson Pharmaceutical Research Institute, Raritan, NJ 08869, USA. bpodloga@prius.jnj.com
authors.forename: B L
authors.initials: BL
authors.lastname: Podlogar
authors.forename: M G
authors.initials: MG
authors.lastname: Paterlini
authors.forename: D M
authors.initials: DM
authors.lastname: Ferguson
authors.forename: G C
authors.initials: GC
authors.lastname: Leo
authors.forename: D A
authors.initials: DA
authors.lastname: Demeter
authors.forename: F K
authors.initials: FK
authors.lastname: Brown
authors.forename: A B
authors.initials: AB
authors.lastname: Reitz
mesh_terms: D003198:Computer Simulation; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry*; D011487:Protein Conformation; D011957:Receptors, Opioid / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013696:Temperature
chemical_list: D009842:Oligopeptides; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; C105293:endomorphin 1