Chatenet, David 
ORCID: https://orcid.org/0000-0002-7270-4328; Dubessy, Christophe; Leprince, Jérôme; Boularan, Cédric; Carlier, Ludovic; Ségalas-Milazzo, Isabelle; Guilhaudis, Laure; Oulyadi, Hassan; Davoust, Daniel; Scalbert, Elizabeth; Pfeiffer, Bruno; Renard, Pierre; Tonon, Marie-Christine; Lihrmann, Isabelle; Pacaud, Pierre et Vaudry, Hubert
(2004).
Structure-activity relationships and structural conformation of a novel urotensin II-related peptide
Peptides
, vol. 25
, nº 10.
pp. 1819-1830.
DOI: 10.1016/j.peptides.2004.04.019.
Résumé
Urotensin II (UII) has been described as the most potent vasoconstrictor peptide and recognized as the endogenous ligand of the orphan G protein-coupled receptor GPR14. Recently, a UII-related peptide (URP) has been isolated from the rat brain and its sequence has been established as H-Ala-Cys-Phe-Trp-Lys-Tyr-Cys-Val-OH. In order to study the structure-function relationships of URP, we have synthesized a series of URP analogs and measured their binding affinity on hGPR14-transfected cells and their contractile activity in a rat aortic ring bioassay. Alanine substitution of each residue of URP significantly reduced the binding affinity and the contractile activity of the peptides, except for the Ala8-substituted analog that retained biological activity. Most importantly, D-scan of URP revealed that [D-Trp4]URP abrogated and [D-Tyr6]URP partially suppressed the UII-evoked contractile response. [Orn5]URP, which had very low agonistic efficacy, was the most potent antagonist in this series. The solution structure of URP has been determined by 1H NMR spectroscopy and molecular dynamics. URP exhibited a single conformation characterized by an inverse gamma-turn comprising residues Trp-Lys-Tyr which plays a crucial role in the biological activity of URP. These pharmacological and structural data should prove useful for the rational design of non-peptide ligands as potential GPR14 agonists and antagonists.
| Type de document: | Article |
|---|---|
| Mots-clés libres: | Urotensin II-related peptide; Urotensin II receptor; Solid-phase peptide synthesis; Ala-scan; d-scan; NMR; Conformational analysis Structure–activity relationships Ligand binding Rat aortic ring contraction |
| Centre: | Centre INRS-Institut Armand Frappier |
| Date de dépôt: | 15 nov. 2024 20:23 |
| Dernière modification: | 15 nov. 2024 20:23 |
| URI: | https://espace.inrs.ca/id/eprint/14488 |
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