Stereochemical requirements for receptor recognition of the μ-opioid peptide endomorphin-1

M. Germana Paterlini, Francesca Avitabile, Beverly Gaul Ostrowski, David M. Ferguson, Philip S. Portoghese

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

Abstract

A series of diastereoisomers of endomorphin-1 (EM1, Tyr1-Pro2-Trp3- Phe4-NH2) have been synthesized and their potency measured using the guinea pig ileum assay. [D-Phe4]EM1 possessed 1/10 the potency of EM1, while potencies of [D-Tyr1]EM1 and [D-Trp3]EM1 were 50- and 100-fold lower, respectively. Drastic loss of activity occurred in the [D-Pro2]EM1 peptide. The structural determinants for the inactivity and reduced potency of the diastereoisomers were investigated using NMR spectroscopy and conformational analysis. Simulations of trans-[D-Pro2]EM1 using NOE-derived distance constraints afforded well-defined structures in which Tyr and Trp side chains stack against the proline ring. The inactivity of [D- Pro2]EM1 was explained by structural comparison with EM1 (Podlogar et al., 1998, FEBS Lett. 439:13- 20). The two peptides showed an opposite orientation of the Trp3 residue with respect to Tyr1, thus suggesting a role of Pro2 as a stereochemical spacer in orienting Trp3 and Phe4 toward regions suitable for μ-receptor interaction. The agonist activity of [D-Tyr1]EM1 and [D-Trp3]EM1 was attributed to their ability to adopt low-energy conformations that mimic those of EM1. The requirements for μ-receptor activation were examined further by comparing EM1 with the μ-peptide [D-Ala2, MePhe4, Gly-ol]- enkephalin (DAMGO). Conformations of DAMGO with a Tyr -MePhe4 phenyl ring separation of ~12 Å, were found to mimic Tyr1-Phe4 of EM1, thus suggesting overlapping binding modes between these two peptides.

Original languageEnglish (US)
Pages (from-to)590-599
Number of pages10
JournalBiophysical journal
Volume78
Issue number2
DOIs
StatePublished - 2000

Bibliographical note

Funding Information:
This work was supported in part by Public Health Service grants DA-00377 (to MGP) and DA-01533 (to PSP). NMR instrumentation was provided with funds from the National Science Foundation (BIR-961477) and the University of Minnesota Medical School.

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