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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.


Eigenvector calulations to predict the stability and structral variations of the simulated complexes.(a) Figure showing the cumulative percentages of the proportional variance contributed by the eigenvectors of the PKR complexes. (b) 2D plot of the projections of the eigenvector 1 and eigenvector 2 showing the essential subspace of the complexes.
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pone.0153680.g005: Eigenvector calulations to predict the stability and structral variations of the simulated complexes.(a) Figure showing the cumulative percentages of the proportional variance contributed by the eigenvectors of the PKR complexes. (b) 2D plot of the projections of the eigenvector 1 and eigenvector 2 showing the essential subspace of the complexes.

Mentions: PCA performed on the simulated ensembles of the six systems as described in methods determines the concerted conformational motions relevant to protein function. The first few eigenvectors from the PCA of the trajectories captured the bulk of the protein dynamics. Fig 5(A) shows the cumulative percentages of the proportional variance contributed by the eigenvectors of the PKR complexes. The first three eigenvectors PKRpp-eIF2α complex capture ninety percent of variance in the protein motions. The other protein complexes require greater number of eigenvectors to capture the similar variance in the PKR motions. This shows that the binding of the substrate eIF2α binding with the PKRpp is more stable than the PKRp form. The inhibitors binding with the PKR forms show a relatively lesser variation than the substrate binding, suggesting that the inhibitors form a stable complex with the PKR proteins.


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)

Eigenvector calulations to predict the stability and structral variations of the simulated complexes.(a) Figure showing the cumulative percentages of the proportional variance contributed by the eigenvectors of the PKR complexes. (b) 2D plot of the projections of the eigenvector 1 and eigenvector 2 showing the essential subspace of the complexes.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0153680.g005: Eigenvector calulations to predict the stability and structral variations of the simulated complexes.(a) Figure showing the cumulative percentages of the proportional variance contributed by the eigenvectors of the PKR complexes. (b) 2D plot of the projections of the eigenvector 1 and eigenvector 2 showing the essential subspace of the complexes.
Mentions: PCA performed on the simulated ensembles of the six systems as described in methods determines the concerted conformational motions relevant to protein function. The first few eigenvectors from the PCA of the trajectories captured the bulk of the protein dynamics. Fig 5(A) shows the cumulative percentages of the proportional variance contributed by the eigenvectors of the PKR complexes. The first three eigenvectors PKRpp-eIF2α complex capture ninety percent of variance in the protein motions. The other protein complexes require greater number of eigenvectors to capture the similar variance in the PKR motions. This shows that the binding of the substrate eIF2α binding with the PKRpp is more stable than the PKRp form. The inhibitors binding with the PKR forms show a relatively lesser variation than the substrate binding, suggesting that the inhibitors form a stable complex with the PKR proteins.

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.