Allosteric Cooperativity in Inhibition of Protein Kinase a Catalytic Subunit

Kuznetsov, Aleksei; Järv, Jaak

doi:10.2174/1874940200801010042

Cited by 4 publications

(9 citation statements)

References 24 publications

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“…This trend had been previously observed, and the principle "better binding: stronger allostery" was formulated [10,11]. This qualitative pattern was formalized in terms of linear freeenergy relationships, as described below.…”

Section: Allosteric Interaction Between Atp and Peptidesmentioning

confidence: 57%

“…Our recent kinetic studies have revealed that the catalytic activity of protein kinase A was indeed governed by interaction between binding sites of two different substrates which can be said to be allosteric [10,11]. Moreover, allosterically regulated ligand binding properties have been observed for this enzyme also in several ligand binding studies, as summarized below.…”

Section: Introductionmentioning

confidence: 91%

“…Different combinations of these parameters characterize formation of the quaternary complex EABI, included into the reaction scheme to depict the most general case. The formation of EABI has also been documented in kinetics of protein kinase inhibition by certain inhibitors [11].…”

Section: Allostery In Reversible Inhibition Of Protein Kinase Amentioning

confidence: 98%

“…Indeed, this enhancement of protein kinase A affinity for ATP has been found experimentally, as the dissociation constant, ranging between 20 and 60 nM, was determined for interaction of ATP with the enzyme-PKI complex [23]. Using the dissociation constant 49 µM for ATP complex with the free catalytic subunit of this enzyme [11], the interaction factor 0.0008 was calculated from these data. This value corresponds well with the results above, calculated from binding data for PKI.…”

Section: Prior Observations Of Protein Kinase a Allosterymentioning

confidence: 99%

“…For PKI(14-22) the inhibition constant 1 µM was mentioned by Lew et al [24], yielding the K i value 6.5 µM. For Ala-kemptide amide (LRRAALG-NH 2 ), K i = 161 µM and γ = 0.3 were directly determined from a complex kinetic study [11]. And finally, Ala-kemptide binding with the enzyme has been assayed in the presence and absence of ATP, yielding the dissociation constants 230 µM and 320 µM, respectively [23].…”

Section: Allosteric Interaction Between Atp and Peptidesmentioning

confidence: 99%

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Ligand structure controlled allostery in cAMP-dependent protein kinase catalytic subunit

Kuznetsov

Järv

2009

Open Life Sciences

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Protein kinase A (cAMP dependent protein kinase catalytic subunit, EC 2.7.11.11) binds simultaneously ATP and a phosphorylatable peptide. These structurally dissimilar allosteric ligands influence the binding effectiveness of each other. The same situation is observed with substrate congeners, which reversibly inhibit the enzyme. In this review these allosteric effects are quantified using the interaction factor, which compares binding effectiveness of ligands with the free enzyme and the pre-loaded enzyme complex containing another ligand. This analysis revealed that the allosteric effect depends upon structure of the interacting ligands, and the principle "better binding: stronger allostery" observed can be formalized in terms of linear free-energy relationships, which point to similar mechanism of the allosteric interaction between the enzyme-bound substrates and/or inhibitor molecules. On the other hand, the type of effect is governed by ligand binding effectiveness and can be inverted from positive allostery to negative allostery if we move from effectively binding ligands to badly binding compounds. Thus the outcome of the allostery in this monomeric enzyme is the same as defined by classical theories for multimeric enzymes: making the enzyme response more efficient if appropriate ligands bind.

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Section: Allosteric Interaction Between Atp and Peptidesmentioning

confidence: 57%

Section: Introductionmentioning

confidence: 91%

Section: Allostery In Reversible Inhibition Of Protein Kinase Amentioning

confidence: 98%

Section: Prior Observations Of Protein Kinase a Allosterymentioning

confidence: 99%

Section: Allosteric Interaction Between Atp and Peptidesmentioning

confidence: 99%

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Ligand structure controlled allostery in cAMP-dependent protein kinase catalytic subunit

Kuznetsov

Järv

2009

Open Life Sciences

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Kinetics of Acrylodan-Labelled cAMP-Dependent Protein Kinase Catalytic Subunit Denaturation

et al. 2013

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Fluorescence spectroscopy was used to study denaturation of cAMP-dependent protein kinase catalytic subunit labeled with an acrylodan moiety. The dye was covalently bound to a cystein residue introduced into the enzyme by replacement of arginine in position 326 in the native sequence, located near the enzyme active center. This labeling had no effect on catalytic activity of the enzyme, but provided possibility to monitor changes in protein structure through measuring the fluorescence spectrum of the dye, which is sensitive to changes in its environment. This method was used to monitor denaturation of the protein kinase catalytic subunit and study the kinetics of this process as well as influence of specific ligands on stability of the protein. Stabilization of the enzyme structure was observed in the presence of adenosine triphosphate, peptide substrate RRYSV and inhibitor peptide PKI[5-24].

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Thermodynamic Aspects of cAMP Dependent Protein Kinase Catalytic Subunit Allostery

2014

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Kinetics of thermal inactivation of acrylodan-labeled cAMP dependent protein kinase catalytic subunit, its binary complexes with ATP and peptide inhibitor PKI[5-24], respectively, and the ternary complex involving both of these ligands were studied at different temperatures (5-50 °C). The thermodynamic parameters ΔH and ΔS for ligand binding equilibria as well as for the allosteric interaction between the binding sites of these ligands were obtained by using the Van't Hoff analysis. The results indicated that more inter- and intra-molecular non-covalent bonds were involved in ATP binding with the protein when compared to the peptide binding. Similarly, nucleotide and peptide binding steps were accompanied with different entropy effects, while almost no entropy change accompanied PKI[5-24] binding, suggesting that the protein flexibility was not affected in this case. Differently from the binary complex formation the ternary complex formation was accompanied by a significant entropy change and with intensive formation of new non-covalent interactions (ΔH). At the same time both ligand binding steps as well as the allosteric interaction between ligand binding sites could be described by a common entropy-enthalpy compensation plot, pointing to a similar mechanism of these phenomena. It was concluded that numerous weak interactions govern the allostery of cAMP dependent protein kinase catalytic subunit.

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Allosteric Cooperativity in Inhibition of Protein Kinase a Catalytic Subunit

Cited by 4 publications

References 24 publications

Ligand structure controlled allostery in cAMP-dependent protein kinase catalytic subunit

Ligand structure controlled allostery in cAMP-dependent protein kinase catalytic subunit

Kinetics of Acrylodan-Labelled cAMP-Dependent Protein Kinase Catalytic Subunit Denaturation

Thermodynamic Aspects of cAMP Dependent Protein Kinase Catalytic Subunit Allostery

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