title: Unraveling the active conformation of urotensin II.
abstract: 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' beta-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 beta-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' beta-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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Salerno, Via Ponte Don Melillo 11C, I-84084 Fisciano, Italy. alfonso.carotenuto@unina.it
authors.forename: Alfonso
authors.initials: A
authors.lastname: Carotenuto
authors.forename: Paolo
authors.initials: P
authors.lastname: Grieco
authors.forename: Pietro
authors.initials: P
authors.lastname: Campiglia
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Paolo
authors.initials: P
authors.lastname: Rovero
mesh_terms: D002839:Chromans / Q000737:chemistry; D002942:Circular Dichroism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry; D010456:Peptides, Cyclic / Q000737:chemistry; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000737:chemistry; D012967:Sodium Dodecyl Sulfate; D012996:Solutions; D013237:Stereoisomerism; D014579:Urotensins / Q000737:chemistry*
chemical_list: C468786:3-(4-chlorophenyl)-3-(2-(dimethylamino)ethyl)isochroman-1-one; D002839:Chromans; D008823:Micelles; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D043562:Receptors, G-Protein-Coupled; D012996:Solutions; C121697:UTS2R protein, human; D014579:Urotensins; C466635:aspartyl-cyclo(penicillamyl-phenylalanyl-tryptophyl-lysyl-tyrosyl-cysteinyl)valine; D012967:Sodium Dodecyl Sulfate; C029677:urotensin II