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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

Cross-correlation heat maps of the PKR protein.Cross-correlation heat map generated using the PCA vectors showing the correlated and anti-correlated regions in the protein structure. The plots are indicated by (a) PKRpp-eIF2α, (b) PKRpp-K3L, (c) PKRpp-TAT, (d) PKRp-eIF2α, (e) PKRp-K3L, (f) PKRp-TAT. The P, N lobes and the activation segment are demarked by a boxed structure.
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pone.0153680.g009: Cross-correlation heat maps of the PKR protein.Cross-correlation heat map generated using the PCA vectors showing the correlated and anti-correlated regions in the protein structure. The plots are indicated by (a) PKRpp-eIF2α, (b) PKRpp-K3L, (c) PKRpp-TAT, (d) PKRp-eIF2α, (e) PKRp-K3L, (f) PKRp-TAT. The P, N lobes and the activation segment are demarked by a boxed structure.

Mentions: To further analyze the altered domain motion of the PKR protein’s N and C-lobe upon interacting with the substrate or inhibitor, a cross-correlation heat map was generated based on the PCA vectors using ProDy python package [58]. Comparing the cross-correlation matrices of different simulation trajectories reveal the similar features shown by the relative motions. Fig 9 shows the cross-correlation matrices of the six protein complexes generated using the PCA eigenvectors. Many regions of the protein, especially the regions of secondary structure, move in a correlated manner [59, 60]. A higher degree of cross correlation among the residues was observed in the PKRp-eIF2α complex followed by the PKRp-K3L complex.


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)

Cross-correlation heat maps of the PKR protein.Cross-correlation heat map generated using the PCA vectors showing the correlated and anti-correlated regions in the protein structure. The plots are indicated by (a) PKRpp-eIF2α, (b) PKRpp-K3L, (c) PKRpp-TAT, (d) PKRp-eIF2α, (e) PKRp-K3L, (f) PKRp-TAT. The P, N lobes and the activation segment are demarked by a boxed structure.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0153680.g009: Cross-correlation heat maps of the PKR protein.Cross-correlation heat map generated using the PCA vectors showing the correlated and anti-correlated regions in the protein structure. The plots are indicated by (a) PKRpp-eIF2α, (b) PKRpp-K3L, (c) PKRpp-TAT, (d) PKRp-eIF2α, (e) PKRp-K3L, (f) PKRp-TAT. The P, N lobes and the activation segment are demarked by a boxed structure.
Mentions: To further analyze the altered domain motion of the PKR protein’s N and C-lobe upon interacting with the substrate or inhibitor, a cross-correlation heat map was generated based on the PCA vectors using ProDy python package [58]. Comparing the cross-correlation matrices of different simulation trajectories reveal the similar features shown by the relative motions. Fig 9 shows the cross-correlation matrices of the six protein complexes generated using the PCA eigenvectors. Many regions of the protein, especially the regions of secondary structure, move in a correlated manner [59, 60]. A higher degree of cross correlation among the residues was observed in the PKRp-eIF2α complex followed by the PKRp-K3L complex.

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