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Unraveling the Active Conformation of Urotensin II

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journal contribution
posted on 25.03.2004, 00:00 by Alfonso Carotenuto, Paolo Grieco, Pietro Campiglia, Ettore Novellino, Paolo Rovero
Urotensin II (U-II) is a disulfide-bridged undecapeptide recently identified as the ligand of an orphan G-protein-coupled receptor. Human U-II (H-Glu-Thr-Pro-Asp-cyclo[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) has been described as the most potent vasoconstrictor compound identified to date.With the aim of elucidating the active conformation of hU-II, we have performed a spectroscopic analysis of hU-II minimal active fragment hU-II(4−11) in different environmental conditions. The analysis indicated that hU-II(4−11) was highly structured in the anisotropic membrane mimetic SDS solution, showing a type II‘ β-turn structure, which is almost unprecedented for l-amino acid peptides. Micelle bound structure of hU-II(4−11) was then compared with those of four synthetic analogues recently synthesized in our lab, bearing modified Cys residues at position 5 and/or position 10 and characterized by different levels of agonist activity. The structures of the active compounds were found to be very similar to that of hU-II(4−11), while a barely active compound does not show any propensity to β-turn formation. Furthermore, distances among putative pharmacophoric points in the structures of the active compounds obtained in SDS solution are in good agreement with those found in a recently described non-peptide agonist of the hU-II receptor. A type II‘ β-turn structure was already found for the somatostatin analogue octreotide. On the basis of the similarity of the primary and 3D structures of U-II and somatostatin analogues and on the basis of the sequence homology between the GPR14/UT-II receptor and members of the somatostatin receptor family, a common evolutionary pathway for the signal transmission system activated by these peptide can be hypothesized.