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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.


Binding energies calulations of PKR with the substrate and the inhibitors.(a) PKR binding energies with the substrate and the inhibitors. The error bars are indicated by black lines. (b) Residue based decomposition of the binding energies for the activation segment of PKR in the PKR complexes.
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pone.0153680.g003: Binding energies calulations of PKR with the substrate and the inhibitors.(a) PKR binding energies with the substrate and the inhibitors. The error bars are indicated by black lines. (b) Residue based decomposition of the binding energies for the activation segment of PKR in the PKR complexes.

Mentions: To further analyze the role of phosphorylation events of PKR molecules we summarized the contribution to the binding affinity of activation loop residues of PKR to the free energy of binding in the Fig 3. Activation loop residues 432, 442, 446, 451 and 458 show a major contribution to the free energy of binding for the PKR and interacting proteins. TAT shows an increase in the binding energies for the major residues 432, 442, 446 and 458 in both the PKRp and PKRpp forms. Thr 451 phosphorylation shows an increased binding free energy contribution than the non-phosphorylation residues with the same protein complexes. Phosphorylation of Thr 451 residue increases the binding energy of both the substrates and the inhibitors with PKRpp contributing to increased binding energy than the PKRp 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)

Binding energies calulations of PKR with the substrate and the inhibitors.(a) PKR binding energies with the substrate and the inhibitors. The error bars are indicated by black lines. (b) Residue based decomposition of the binding energies for the activation segment of PKR in the PKR complexes.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0153680.g003: Binding energies calulations of PKR with the substrate and the inhibitors.(a) PKR binding energies with the substrate and the inhibitors. The error bars are indicated by black lines. (b) Residue based decomposition of the binding energies for the activation segment of PKR in the PKR complexes.
Mentions: To further analyze the role of phosphorylation events of PKR molecules we summarized the contribution to the binding affinity of activation loop residues of PKR to the free energy of binding in the Fig 3. Activation loop residues 432, 442, 446, 451 and 458 show a major contribution to the free energy of binding for the PKR and interacting proteins. TAT shows an increase in the binding energies for the major residues 432, 442, 446 and 458 in both the PKRp and PKRpp forms. Thr 451 phosphorylation shows an increased binding free energy contribution than the non-phosphorylation residues with the same protein complexes. Phosphorylation of Thr 451 residue increases the binding energy of both the substrates and the inhibitors with PKRpp contributing to increased binding energy than the PKRp 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.