title: Allosteric Effect of Adenosine Triphosphate on Peptide Recognition by 3'5'-Cyclic Adenosine Monophosphate Dependent Protein Kinase Catalytic Subunits.
abstract: The allosteric influence of adenosine triphosphate (ATP) on the binding effectiveness of a series of peptide inhibitors with the catalytic subunit of 3'5'-cyclic adenosine monophosphate dependent protein kinase was investigated, and the dependence of this effect on peptide structure was analyzed. The allosteric effect was calculated as ratio of peptide binding effectiveness with the enzyme-ATP complex and with the free enzyme, quantified by the competitive inhibition of the enzyme in the presence of ATP excess, and by the enzyme-peptide complex denaturation assay, respectively It was found that the principle "better binding-stronger allostery" holds for interactions of the studied peptides with the enzyme, indicating that allostery and peptide binding with the free enzyme are governed by the same specificity pattern. This means that the allosteric regulation does not include new ligand-protein interactions, but changes the intensity (strength) of the interatomic forces that govern the complex formation in the case of each individual ligand. We propose that the allosteric regulation can be explained by the alteration of the intrinsic dynamics of the protein by ligand binding, and that this phenomenon, in turn, modulates the ligand off-rate from its binding site as well as the binding affinity. The positive allostery could therefore be induced by a reduction in the enzyme's overall intrinsic dynamics.
authors.affiliation: Institute of Chemistry, University of Tartu, Tartu, Estonia.|Institute of Technology, University of Tartu, Tartu, Estonia.
authors.forename: Rait
authors.initials: R
authors.lastname: Kivi
authors.affiliation: Institute of Chemistry, University of Tartu, Tartu, Estonia.|CEITEC - Central European Institute of Technology, Masaryk University, Kamenice 753/5, 625 00, Brno, Czech Republic.
authors.forename: Karina
authors.initials: K
authors.lastname: Solovjova
authors.affiliation: Institute of Chemistry, University of Tartu, Tartu, Estonia.
authors.forename: Tõiv
authors.initials: T
authors.lastname: Haljasorg
authors.affiliation: Institute of Technology, University of Tartu, Tartu, Estonia.
authors.forename: Piret
authors.initials: P
authors.lastname: Arukuusk
authors.affiliation: Institute of Chemistry, University of Tartu, Tartu, Estonia. jaak.jarv@ut.ee.
authors.forename: Jaak
authors.initials: J
authors.lastname: Järv
mesh_terms: D015081:2-Naphthylamine / Q000031:analogs & derivatives / Q000737:chemistry; D000255:Adenosine Triphosphate / Q000737:chemistry* / Q000378:metabolism; D000494:Allosteric Regulation; D000495:Allosteric Site; D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D000242:Cyclic AMP / Q000737:chemistry* / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008024:Ligands; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D013194:Staining and Labeling / Q000379:methods; D013816:Thermodynamics
chemical_list: D005456:Fluorescent Dyes; D008024:Ligands; D010455:Peptides; D047428:Protein Kinase Inhibitors; C038518:acrylodan; D000255:Adenosine Triphosphate; D015081:2-Naphthylamine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: ATP binding; Allosteric regulation mechanism; Ligand structure effect; Peptide binding; cAMP-dependent protein kinase catalytic subunit