Urotensin-II and URP. What can we learn from ligand conformation?

The urotensin II receptor (UT) has long been studied mainly for its involvement in the cardiovascular homeostasis in either health or disease state [1]. The biological activities associated with UT activation are modulated by two endogenous ligands, i.e. urotensin II (UII) and urotensin II-related peptide (URP). Extensive expression of the two ligands revealed the multiple pathophysiological effects mediated by the urotensin system such as cardiovascular disorders (heart failure, cardiac remodelling, hypertension), smooth muscle cell proliferation, renal disease, diabetes, and tumour growth. As recently demonstrated, UII and URP could exert different actions on transcriptional activity, cell proliferation, and myocardial contractile activities supporting the idea that UII and URP interact with UT in a distinct manner (biased agonism). We have developed a number of UII analogs, among which a superagonist named P5U and an antagonist named urantide. Conformational studies, mainly by solution NMR, on novel developed UII analogs and URP reveal detailed information on the bound structure of agonists and antagonists at UT and can help to elucidate the different activation mechanisms of URP and UII.