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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

Structral stability of the PKR complexes.The time dependent variations of PKR forms in complex with the substrates and inhibitors. (a) shows the RMSD of the backbone atoms (b) RMSF fluctuation of the PKR residues (c) Radius of gyration of PKR forms in the complexes. Residues showing higher RMSF values are marked in the figure.
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pone.0153680.g001: Structral stability of the PKR complexes.The time dependent variations of PKR forms in complex with the substrates and inhibitors. (a) shows the RMSD of the backbone atoms (b) RMSF fluctuation of the PKR residues (c) Radius of gyration of PKR forms in the complexes. Residues showing higher RMSF values are marked in the figure.

Mentions: The resultant trajectories of the MDS studies were further analyzed using root mean square deviation (RMSD), root mean square fluctuation (RMSF), and radius of gyration (Rg) using g_rmsd, g_sas, and g_gyrate GROMACS utilities respectively, were shown in Fig 1. RMSD and Radius of Gyration (Rg) values of the trajectory files produced a stable plot after 10 ns of simulation with a fluctuation range lesser than 2Å, thus providing the suitability to carry out the further analysis. eIF2α bound PKRp and PKRpp molecules show rmsd plots with lesser fluctuations at 4 Å and 6 Å respectively. The rmsd plots of inhibitor bound complexes show a range of fluctuations ranging from 3 Å to 7 Å except the PKRp-TAT form which shows a lesser fluctuation at the 5 Å range due to its smaller surface area. The rmsd plots provide insight how the substrate binding equilibrated the system than the inhibitor molecules.


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)

Structral stability of the PKR complexes.The time dependent variations of PKR forms in complex with the substrates and inhibitors. (a) shows the RMSD of the backbone atoms (b) RMSF fluctuation of the PKR residues (c) Radius of gyration of PKR forms in the complexes. Residues showing higher RMSF values are marked in the figure.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0153680.g001: Structral stability of the PKR complexes.The time dependent variations of PKR forms in complex with the substrates and inhibitors. (a) shows the RMSD of the backbone atoms (b) RMSF fluctuation of the PKR residues (c) Radius of gyration of PKR forms in the complexes. Residues showing higher RMSF values are marked in the figure.
Mentions: The resultant trajectories of the MDS studies were further analyzed using root mean square deviation (RMSD), root mean square fluctuation (RMSF), and radius of gyration (Rg) using g_rmsd, g_sas, and g_gyrate GROMACS utilities respectively, were shown in Fig 1. RMSD and Radius of Gyration (Rg) values of the trajectory files produced a stable plot after 10 ns of simulation with a fluctuation range lesser than 2Å, thus providing the suitability to carry out the further analysis. eIF2α bound PKRp and PKRpp molecules show rmsd plots with lesser fluctuations at 4 Å and 6 Å respectively. The rmsd plots of inhibitor bound complexes show a range of fluctuations ranging from 3 Å to 7 Å except the PKRp-TAT form which shows a lesser fluctuation at the 5 Å range due to its smaller surface area. The rmsd plots provide insight how the substrate binding equilibrated the system than the inhibitor molecules.

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