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Viral Evolved Inhibition Mechanism of the RNA Dependent Protein Kinase PKR's Kinase Domain, a Structural Perspective.

Krishna KH, Vadlamudi Y, Kumar MS - PLoS ONE (2016)

Bottom Line: In addition, PKR exhibits variations in the secondary structural transition of the activation loop residues, and inter molecular contacts with the substrate and the inhibitors.Phosphorylation of the P+1 loop at the Thr-451 increases the affinity of the binding proteins exhibiting its role in the phosphorylation events.The implications of structural mechanisms uncovered will help to understand the basis of the evolution of the host-viral and the viral replication mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Centre for Bioinformatics, Pondicherry University, Kalapet, Pondicherry, India.

ABSTRACT
The protein kinase PKR activated by viral dsRNA, phosphorylates the eIF2α, which inhibit the mechanism of translation initiation. Viral evolved proteins mimicking the eIF2α block its phosphorylation and help in the viral replication. To decipher the molecular basis for the PKR's substrate and inhibitor interaction mechanisms, we carried the molecular dynamics studies on the catalytic domain of PKR in complex with substrate eIF2α, and inhibitors TAT and K3L. The studies conducted show the altered domain movements of N lobe, which confers open and close state to the substrate-binding cavity. In addition, PKR exhibits variations in the secondary structural transition of the activation loop residues, and inter molecular contacts with the substrate and the inhibitors. Phosphorylation of the P+1 loop at the Thr-451 increases the affinity of the binding proteins exhibiting its role in the phosphorylation events. The implications of structural mechanisms uncovered will help to understand the basis of the evolution of the host-viral and the viral replication mechanisms.

No MeSH data available.


Related in: MedlinePlus

Electrostatic potential maps of the binding surfaces of PKR complexes.The electrostatic potential maps of the binding surfaces along with the activation loop of PKR are shown for the selected stuctres from the free energy landscape plot. Figs 1, 3 and 5 indicate PKRpp bound to eIF2α, K3L and TAT. Figs 2, 4 and 6 indicate PKRp bound to eIF2α, K3L and TAT. The region in red color indicate high electronegative regions and the regions in blue color indicate electropositive regions. The color bars are calibrated in kcal/mol/e.
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pone.0153680.g007: Electrostatic potential maps of the binding surfaces of PKR complexes.The electrostatic potential maps of the binding surfaces along with the activation loop of PKR are shown for the selected stuctres from the free energy landscape plot. Figs 1, 3 and 5 indicate PKRpp bound to eIF2α, K3L and TAT. Figs 2, 4 and 6 indicate PKRp bound to eIF2α, K3L and TAT. The region in red color indicate high electronegative regions and the regions in blue color indicate electropositive regions. The color bars are calibrated in kcal/mol/e.

Mentions: The electrostatic potential maps of the binding surface area along with the aloop of PKR protein for the above selected structures from free energy landscape plot were generated using the Delphi [53] plugin of UCSF Chimera [54] program. The maps show an altered potentials for the same protein derived from the varied energy bins. The electrostatic potential maps shown in the Fig 7 provide insight to the distribution of the charge potentials on the binding surface. The PKRpp forms show an increased electropositive potential in the PKR interaction surface along with its activation loop than that of the PKRp forms. The eIF2α substrate shows a high-density electronegative region in both the PKR forms, which aids in the retention of the binding interaction with the PKR forms. The inhibitors proteins show a minor electronegativity patch with a lesser variations on the electron density scales. In addition the inhibitors are dominated by a predominant electropositive surface area similar to the PKR forms which inhibits the transfer of a charge moiety. On the other hand, the substrate eIF2α maintains good electro potential balance in both the PKR complexes. The PKRpp form comparable to PKRp form shows an increased electropositive nature due to the presence of additional phosphate group which helps in the phosphorylation of the eIF2α.


Viral Evolved Inhibition Mechanism of the RNA Dependent Protein Kinase PKR's Kinase Domain, a Structural Perspective.

Krishna KH, Vadlamudi Y, Kumar MS - PLoS ONE (2016)

Electrostatic potential maps of the binding surfaces of PKR complexes.The electrostatic potential maps of the binding surfaces along with the activation loop of PKR are shown for the selected stuctres from the free energy landscape plot. Figs 1, 3 and 5 indicate PKRpp bound to eIF2α, K3L and TAT. Figs 2, 4 and 6 indicate PKRp bound to eIF2α, K3L and TAT. The region in red color indicate high electronegative regions and the regions in blue color indicate electropositive regions. The color bars are calibrated in kcal/mol/e.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835081&req=5

pone.0153680.g007: Electrostatic potential maps of the binding surfaces of PKR complexes.The electrostatic potential maps of the binding surfaces along with the activation loop of PKR are shown for the selected stuctres from the free energy landscape plot. Figs 1, 3 and 5 indicate PKRpp bound to eIF2α, K3L and TAT. Figs 2, 4 and 6 indicate PKRp bound to eIF2α, K3L and TAT. The region in red color indicate high electronegative regions and the regions in blue color indicate electropositive regions. The color bars are calibrated in kcal/mol/e.
Mentions: The electrostatic potential maps of the binding surface area along with the aloop of PKR protein for the above selected structures from free energy landscape plot were generated using the Delphi [53] plugin of UCSF Chimera [54] program. The maps show an altered potentials for the same protein derived from the varied energy bins. The electrostatic potential maps shown in the Fig 7 provide insight to the distribution of the charge potentials on the binding surface. The PKRpp forms show an increased electropositive potential in the PKR interaction surface along with its activation loop than that of the PKRp forms. The eIF2α substrate shows a high-density electronegative region in both the PKR forms, which aids in the retention of the binding interaction with the PKR forms. The inhibitors proteins show a minor electronegativity patch with a lesser variations on the electron density scales. In addition the inhibitors are dominated by a predominant electropositive surface area similar to the PKR forms which inhibits the transfer of a charge moiety. On the other hand, the substrate eIF2α maintains good electro potential balance in both the PKR complexes. The PKRpp form comparable to PKRp form shows an increased electropositive nature due to the presence of additional phosphate group which helps in the phosphorylation of the eIF2α.

Bottom Line: In addition, PKR exhibits variations in the secondary structural transition of the activation loop residues, and inter molecular contacts with the substrate and the inhibitors.Phosphorylation of the P+1 loop at the Thr-451 increases the affinity of the binding proteins exhibiting its role in the phosphorylation events.The implications of structural mechanisms uncovered will help to understand the basis of the evolution of the host-viral and the viral replication mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Centre for Bioinformatics, Pondicherry University, Kalapet, Pondicherry, India.

ABSTRACT
The protein kinase PKR activated by viral dsRNA, phosphorylates the eIF2α, which inhibit the mechanism of translation initiation. Viral evolved proteins mimicking the eIF2α block its phosphorylation and help in the viral replication. To decipher the molecular basis for the PKR's substrate and inhibitor interaction mechanisms, we carried the molecular dynamics studies on the catalytic domain of PKR in complex with substrate eIF2α, and inhibitors TAT and K3L. The studies conducted show the altered domain movements of N lobe, which confers open and close state to the substrate-binding cavity. In addition, PKR exhibits variations in the secondary structural transition of the activation loop residues, and inter molecular contacts with the substrate and the inhibitors. Phosphorylation of the P+1 loop at the Thr-451 increases the affinity of the binding proteins exhibiting its role in the phosphorylation events. The implications of structural mechanisms uncovered will help to understand the basis of the evolution of the host-viral and the viral replication mechanisms.

No MeSH data available.


Related in: MedlinePlus