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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

Domain movements of PKR in the protein protein complexes.Effective rotation axes and perpendicular centroid-connecting lines are rendered as tubes in the color of the corresponding domain. The arrows indicate a left-hand rotation, indicating a shift in the center of mass of the domain from the first structure to the second structure. The plots are indicated by (a) PKRpp-eIF2α, (b) PKRpp-K3L, (c) PKRpp-TAT, (d) PKRp-eIF2α, (e) PKRp-K3L, (f) PKRp-TAT. Reference domain, Domain 1 and Domain 2 are indicated by Blue, Red and Black respectively. The arrows drawn indicate the direction of the domain motion.
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pone.0153680.g008: Domain movements of PKR in the protein protein complexes.Effective rotation axes and perpendicular centroid-connecting lines are rendered as tubes in the color of the corresponding domain. The arrows indicate a left-hand rotation, indicating a shift in the center of mass of the domain from the first structure to the second structure. The plots are indicated by (a) PKRpp-eIF2α, (b) PKRpp-K3L, (c) PKRpp-TAT, (d) PKRp-eIF2α, (e) PKRp-K3L, (f) PKRp-TAT. Reference domain, Domain 1 and Domain 2 are indicated by Blue, Red and Black respectively. The arrows drawn indicate the direction of the domain motion.

Mentions: The substrates and the inhibitors bound to the protein in the complex induce the conformational transitions hinge bending which involves the movement of relatively rigid parts of a protein about flexible joints. Hingefind [55] an algorithm partitions a protein into domains of preserved geometry and subsequently characterizes the relative movements of the found domains by effective rotation axes (hinges). The residues involved in the domain organization are the axis of rotation of the Domain II and I pass through the N lobe of the PKR molecule, which exemplifies that the conformational change of domain opening in the PKR protein was induced, by the flexible N lobes. Fig 8 shows the domain motion of the PKR protein along with their rotational directions.


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)

Domain movements of PKR in the protein protein complexes.Effective rotation axes and perpendicular centroid-connecting lines are rendered as tubes in the color of the corresponding domain. The arrows indicate a left-hand rotation, indicating a shift in the center of mass of the domain from the first structure to the second structure. The plots are indicated by (a) PKRpp-eIF2α, (b) PKRpp-K3L, (c) PKRpp-TAT, (d) PKRp-eIF2α, (e) PKRp-K3L, (f) PKRp-TAT. Reference domain, Domain 1 and Domain 2 are indicated by Blue, Red and Black respectively. The arrows drawn indicate the direction of the domain motion.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0153680.g008: Domain movements of PKR in the protein protein complexes.Effective rotation axes and perpendicular centroid-connecting lines are rendered as tubes in the color of the corresponding domain. The arrows indicate a left-hand rotation, indicating a shift in the center of mass of the domain from the first structure to the second structure. The plots are indicated by (a) PKRpp-eIF2α, (b) PKRpp-K3L, (c) PKRpp-TAT, (d) PKRp-eIF2α, (e) PKRp-K3L, (f) PKRp-TAT. Reference domain, Domain 1 and Domain 2 are indicated by Blue, Red and Black respectively. The arrows drawn indicate the direction of the domain motion.
Mentions: The substrates and the inhibitors bound to the protein in the complex induce the conformational transitions hinge bending which involves the movement of relatively rigid parts of a protein about flexible joints. Hingefind [55] an algorithm partitions a protein into domains of preserved geometry and subsequently characterizes the relative movements of the found domains by effective rotation axes (hinges). The residues involved in the domain organization are the axis of rotation of the Domain II and I pass through the N lobe of the PKR molecule, which exemplifies that the conformational change of domain opening in the PKR protein was induced, by the flexible N lobes. Fig 8 shows the domain motion of the PKR protein along with their rotational directions.

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