Computer modeling of the dynamic properties of the cAMP-dependent protein kinase catalytic subunit

Izvolski, Andrei; Järv, Jaak; Kuznetsov, Aleksei

doi:10.1016/j.compbiolchem.2013.06.004

Cited by 3 publications

(4 citation statements)

References 27 publications

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“…It was further found that ligand binding with the enzyme reduced the conformational dynamics of the PKAc mol ecule, and most interestingly, this effect was not localized within the binding sites but was permeated through the whole protein molecule (Li et al 2014). Similar results were also obtained in our previous work, demonstrating that the enzymebound ATP changed the structure of the peptide binding site, and that the peptide binding also affected the structure of the ATP binding site (Izvolski et al 2013). However, in addition to these results, the present study provides a unique opportunity to analyze the depen d ence of the conformational dynamics of the PKAc mol ecule upon ligand structure and binding effectiveness.…”

Section: Influence Of Peptide Binding On Protein Conformational Dynamicssupporting

confidence: 83%

“…Two physiologically meaningful Mg ions, which were replaced by Mn ions for the Xray analysis, were also restored in the protein structures. All these procedures were described in detail in our previous paper (Izvolski et al 2013). The peptide and ATP structures were prepared by ChemSketch version 12 software (Advanced Chemistry Development, Inc., Canada) and PyMOL Molecular Graphics System version 1.6 (Schrödinger, LLC, USA) and optimized by molecular dynamics cal culations.…”

Section: Initial Files For Computational Analysismentioning

confidence: 99%

“…In the first stage of the in silico binding study, the initial structures of the free PKAc and the ATP complex with this enzyme were optimized by molecular dynamics (1) calculations until the RMSD value leveled off after 60-100 ns. Then the most populated structural clusters of the free enzyme and the enzyme-ATP complex were se lected (Izvolski et al 2013) and were used for peptide docking. The relevant peptide positions were selected from the docking results, proceeding from the stereo chemistry of the phosphoryl group transfer reaction, which requires close positioning of the serine OH group and the γphosphorus atom of ATP at a distance no greater than 5Å (Wang and Cole 2014).…”

Section: Computational Analysis Of Peptide Binding With Pkacmentioning

confidence: 99%

“…In the next step, the structures of the protein-peptide and protein-ATP-peptide complexes were again opti mized by molecular dynamics calculations, and the most popu lated clusters of these structures were selected (Izvolski et al 2013). Thereafter, the bound peptide was deleted from these optimized structures to obtain a new input file for the next docking step.…”

Section: Computational Analysis Of Peptide Binding With Pkacmentioning

confidence: 99%

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Computational modeling of cAMP-dependent protein kinase allostery

Izvolski,

Kuznetsov

2023

PEAS

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The classical models of allostery were formulated for oligomeric proteins, assuming that effector binding affects substrate binding on another subunit (Monod et al. 1965;Koshland et al. 1966). Later, the concept of allostery was extended to monomeric proteins, which have distinct binding sites for two ligands. This definition also includes bisubstrate enzymes (Cui and Karplus 2008;Laskowski et al. 2009; CornishBowden 2014;Changeux 2011). Protein kinases belong to this group of enzymes as the in line transfer of a phosphoryl group from ATP to a phos phorylatable peptide/protein assumes that both these substrates are simultaneously bound with the enzyme (Wang and Cole 2014). Direct evidence that allosteric interaction between ATP and the peptide substrate binding sites manifests in the catalytic subunit of cAMPdepen dent protein kinase (PKAc) was presented by Masterson et al. (2008). Thereafter, the idea of allosteric regulation in PKAc was expanded by Kuznetsov and Järv (2009),

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Section: Influence Of Peptide Binding On Protein Conformational Dynamicssupporting

confidence: 83%

Section: Initial Files For Computational Analysismentioning

confidence: 99%

Section: Computational Analysis Of Peptide Binding With Pkacmentioning

confidence: 99%

Section: Computational Analysis Of Peptide Binding With Pkacmentioning

confidence: 99%

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Computational modeling of cAMP-dependent protein kinase allostery

Izvolski,

Kuznetsov

2023

PEAS

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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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Computational modeling of acrylodan-labeled cAMP dependent protein kinase catalytic subunit unfolding

Kuznetsov

Kivi

Järv

2016

Computational Biology and Chemistry

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Computer modeling of the dynamic properties of the cAMP-dependent protein kinase catalytic subunit

Cited by 3 publications

References 27 publications

Computational modeling of cAMP-dependent protein kinase allostery

Computational modeling of cAMP-dependent protein kinase allostery

Thermodynamic Aspects of cAMP Dependent Protein Kinase Catalytic Subunit Allostery

Computational modeling of acrylodan-labeled cAMP dependent protein kinase catalytic subunit unfolding

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Computer modeling of the dynamic properties of the cAMP-dependent protein kinase catalytic subunit

Cited by 3 publications

References 27 publications

Computational modeling of cAMP­-dependent protein kinase allostery

Computational modeling of cAMP­-dependent protein kinase allostery

Thermodynamic Aspects of cAMP Dependent Protein Kinase Catalytic Subunit Allostery

Computational modeling of acrylodan-labeled cAMP dependent protein kinase catalytic subunit unfolding

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Computational modeling of cAMP-dependent protein kinase allostery

Computational modeling of cAMP-dependent protein kinase allostery