An investigation into the origin of the biased agonism associated with the urotensin II receptor activation

• Published in: Journal of peptide science Vol. 21; no. 5; pp. 392 - 399
• Main Authors: Brancaccio, Diego, Merlino, Francesco, Limatola, Antonio, Yousif, Ali Munaim, Gomez-Monterrey, Isabel, Campiglia, Pietro, Novellino, Ettore, Grieco, Paolo, Carotenuto, Alfonso
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.05.2015; Wiley Subscription Services, Inc
• Subjects: Amino Acid Sequence; Animals; biased agonism; conformation by NMR; docking studies; Humans; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Docking Simulation; Peptide Hormones - agonists; Peptide Hormones - chemical synthesis; Peptide Hormones - chemistry; Peptide Hormones - metabolism; Peptides; Protein Conformation; Receptors, G-Protein-Coupled - chemistry; Receptors, G-Protein-Coupled - metabolism; Sodium Dodecyl Sulfate - chemistry; Structure-Activity Relationship; therapeutic peptide; urotensin II-related peptide; urotensin-II; Urotensins - agonists; Urotensins - chemistry; Urotensins - metabolism; conformation by NMR; docking studies; biased agonism; urotensin II-related peptide; urotensin-II; therapeutic peptide
• ISSN: 1075-2617; 1099-1387
• DOI: 10.1002/psc.2740

The urotensin II receptor (UTR) has long been studied mainly for its involvement in the cardiovascular homeostasis both in health and disease state. Two endogenous ligands activate UTR, i.e. urotensin II (U‐II) and urotensin II‐related peptide (URP). Extensive expression of the two ligands uncovers the diversified pathophysiological effects mediated by the urotensinergic system such as cardiovascular disorders, smooth muscle cell proliferation, renal disease, diabetes, and tumour growth. As newly reported, U‐II and URP have distinct effects on transcriptional activity, cell proliferation, and myocardial contractile activities supporting the idea that U‐II and URP interact with UTR in a distinct manner (biased agonism). To shed light on the origin of the divergent activities of the two endogenous ligands, we performed a conformational study on URP by solution NMR in sodium dodecyl sulfate micelle solution and compared the obtained NMR structure of URP with that of hU‐II previously determined. Finally, we undertook docking studies between URP, hU‐II, and an UT receptor model. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd. The urotensin II receptor (UTR) has long been studied mainly for its involvement in the cardiovascular homeostosis. The endogenous ligands of UTR, U‐II, and URP can exert common as well as different actions (biased agonism). To shed light on the origin of the divergent activities of two endogenous ligands, we performed a conformational study on URP, compared the obtained NMR structure of URP with that of hU‐II previously determined, and undertook docking studies between URP, hU‐II, and a newly developed UT receptor model.