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


ABSTRACT: The protein kinase PKR activated by viral dsRNA, phosphorylates the eIF2?, which inhibit the mechanism of translation initiation. Viral evolved proteins mimicking the eIF2? 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 eIF2?, 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.

SUBMITTER: Krishna KH 

PROVIDER: S-EPMC4835081 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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

Krishna K Hari KH   Vadlamudi Yallamandayya Y   Kumar Muthuvel Suresh MS  

PloS one 20160418 4


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  ...[more]

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