| Abstract
| - Urotensin II (U-II) is a disulfide-bridged undecapeptide recently identified as the ligand of anorphan 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 identifiedto date.With the aim of elucidating the active conformation of hU-II, we have performed aspectroscopic analysis of hU-II minimal active fragment hU-II(4−11) in different environmentalconditions. The analysis indicated that hU-II(4−11) was highly structured in the anisotropicmembrane mimetic SDS solution, showing a type II‘ β-turn structure, which is almostunprecedented for l-amino acid peptides. Micelle bound structure of hU-II(4−11) was thencompared with those of four synthetic analogues recently synthesized in our lab, bearingmodified Cys residues at position 5 and/or position 10 and characterized by different levels ofagonist activity. The structures of the active compounds were found to be very similar to thatof hU-II(4−11), while a barely active compound does not show any propensity to β-turnformation. Furthermore, distances among putative pharmacophoric points in the structures ofthe active compounds obtained in SDS solution are in good agreement with those found in arecently described non-peptide agonist of the hU-II receptor. A type II‘ β-turn structure wasalready found for the somatostatin analogue octreotide. On the basis of the similarity of theprimary and 3D structures of U-II and somatostatin analogues and on the basis of the sequencehomology 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 peptidecan be hypothesized.
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