title: Effect of two simultaneous aza-β3-amino acid substitutions on recognition of peptide substrates by cAMP dependent protein kinase catalytic subunit.
abstract: Peptidomimetic analogs of the hexapeptide RRASVA, containing simultaneously two aza-β(3)-amino acid residues in different positions of this sequence, except for the phosphorylatable serine residue, were synthesized and tested as substrates for the cAMP-dependent protein kinase catalytic subunit. All these peptidomimetics were phosphorylated by the enzyme and this reaction was characterized by the K(m) and k(cat) values as well as by the second-order rate constants k(II). Affinity and reactivity of all peptidomimetics was lower than that for the parent peptide RRASVA. The effect of backbone modification was dependent upon the positions where these two aza-β(3) residues were located, although the sequence of amino acid side groups remained the same in all compounds. It was found that the influence of two backbone modifications in the substrate structure was not described additively, i.e. the effect of each structural alteration was dependent upon the position of the second modification. The results were in agreement with the concept of specificity-determining clusters in the sequence of peptide and peptidomimetic ligands, which predominantly determine the molecular recognition of these ligands by their target sites and therefore serve as major modification points for the design of activity of peptidomimetic ligands.
authors.affiliation: Institute of Chemistry, University of Tartu, Ravila 14a, Tartu 50411, Estonia.
authors.forename: Ksenija
authors.initials: K
authors.lastname: Kisseljova
authors.forename: Aleksei
authors.initials: A
authors.lastname: Kuznetsov
authors.forename: Michèle
authors.initials: M
authors.lastname: Baudy-Floc'h
authors.forename: Jaak
authors.initials: J
authors.lastname: Järv
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry*; D001372:Aza Compounds / Q000737:chemistry*; D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry* / Q000378:metabolism*; D007700:Kinetics; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D057786:Peptidomimetics; D010766:Phosphorylation; D013379:Substrate Specificity
chemical_list: D000596:Amino Acids; D001372:Aza Compounds; D010455:Peptides; D057786:Peptidomimetics; D017868:Cyclic AMP-Dependent Protein Kinases