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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.


Free energy landscapes of the PKR protein complexes.The plots are indicated by (a) PKRpp-eIF2α, (b) PKRpp-K3L, (c) PKRpp-TAT, (d) PKRp- eIF2α, (e) PKRp-K3L, (f) PKRp-TAT. Conformations having lower energies retrieved from the Free energy landscapes are marked with a dot in the square. The energy bars indicate binding free energy in KJ/mol.
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pone.0153680.g006: Free energy landscapes of the PKR protein complexes.The plots are indicated by (a) PKRpp-eIF2α, (b) PKRpp-K3L, (c) PKRpp-TAT, (d) PKRp- eIF2α, (e) PKRp-K3L, (f) PKRp-TAT. Conformations having lower energies retrieved from the Free energy landscapes are marked with a dot in the square. The energy bars indicate binding free energy in KJ/mol.

Mentions: The first two principal component vectors were considered for the construction of the free energy landscapes (FELs). Free energy landscapes of the PKR protein complexes generated were shown in Fig 6. The higher peak in the energy profile reflects the higher stable protein complexes in the simulation trajectory. The FELs were quite different among the six systems; in particular, their energy bins were located in different regions. The PKRpp-eIF2α complex shows a two prominent energy bins on the left side and an energy bin with lesser depth energy bins on the right side. The PKRp-eIF2α has a widespread energy bin on the left side and a discontinuous energy bin spanning on the right side. The PKRpp-K3L has a smaller energy bin on the left side and two-energy bins one spanning lesser area and the other having a wider area with deeper energy bin was on the right side. The PKRp-K3L energy bins on the right side have a smaller spanning area and on to the right side was a major spanning bin with discontinuous energy distributions. The TAT complexes with the PKRpp and PKRp have energy bins spanning from the left side to the left with discontinuous energy distributions. The two least energy conformations depicting the major conformational states of the complexes were retrieved from the trajectory file and used for further analysis.


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)

Free energy landscapes of the PKR protein complexes.The plots are indicated by (a) PKRpp-eIF2α, (b) PKRpp-K3L, (c) PKRpp-TAT, (d) PKRp- eIF2α, (e) PKRp-K3L, (f) PKRp-TAT. Conformations having lower energies retrieved from the Free energy landscapes are marked with a dot in the square. The energy bars indicate binding free energy in KJ/mol.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0153680.g006: Free energy landscapes of the PKR protein complexes.The plots are indicated by (a) PKRpp-eIF2α, (b) PKRpp-K3L, (c) PKRpp-TAT, (d) PKRp- eIF2α, (e) PKRp-K3L, (f) PKRp-TAT. Conformations having lower energies retrieved from the Free energy landscapes are marked with a dot in the square. The energy bars indicate binding free energy in KJ/mol.
Mentions: The first two principal component vectors were considered for the construction of the free energy landscapes (FELs). Free energy landscapes of the PKR protein complexes generated were shown in Fig 6. The higher peak in the energy profile reflects the higher stable protein complexes in the simulation trajectory. The FELs were quite different among the six systems; in particular, their energy bins were located in different regions. The PKRpp-eIF2α complex shows a two prominent energy bins on the left side and an energy bin with lesser depth energy bins on the right side. The PKRp-eIF2α has a widespread energy bin on the left side and a discontinuous energy bin spanning on the right side. The PKRpp-K3L has a smaller energy bin on the left side and two-energy bins one spanning lesser area and the other having a wider area with deeper energy bin was on the right side. The PKRp-K3L energy bins on the right side have a smaller spanning area and on to the right side was a major spanning bin with discontinuous energy distributions. The TAT complexes with the PKRpp and PKRp have energy bins spanning from the left side to the left with discontinuous energy distributions. The two least energy conformations depicting the major conformational states of the complexes were retrieved from the trajectory file and used for further analysis.

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.