Limits...
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.


Number of intermolecular hydrogen bonds formed by PKR.The plot showing the number of hydrogen bonds between PKR and the interacting proteins in a time dependent manner.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4835081&req=5

pone.0153680.g002: Number of intermolecular hydrogen bonds formed by PKR.The plot showing the number of hydrogen bonds between PKR and the interacting proteins in a time dependent manner.

Mentions: Hydrogen bonding numbers in protein—protein interactions confers rigidity to the protein structure and specificity of intermolecular interactions. Fig 2 shows the numbers of Hydrogen bonds formed between PKR and proteins in the complex. TAT complex shows an increased number of H-bonds with both forms of PKR. The substrate eIF2α shows a good tendency of H bonding patterns with PKRpp and shows a rapid fall in numbers for PKRp. Inhibitor K3L due to the substrate-mimicking feature exhibits an equal number of H-bonds. The TAT protein interacts with the N lobe terminal α-helices and C lobe αD helices showing an increase number of H bond formation than the other protein complexes. The αG lobe and the N lobe terminal α-helices of the PKRpp protein shows an increased H bond formation than the PKRp protein with the eIF2α which contributes to the increased H bonds numbers of PKRpp-eIF2α complex. The PKRpp-K3L protein complex exhibits H bond formations between phosphorylated Thr 446 and His 47 of the K3L protein. Other protein complexes lack interactions with Thr 446 of the PKR. The double phosphorylated PKRpp-eIF2α, PKRpp-K3L, PKRpp-TAT forms show H-bond formations of phosphorylated Thr with the Arg 54, Arg 56, and Ser57 of eif2α, Lys 45 of K3L; and Lys 28 and Tyr32 of TAT. The phosphorylated Thr 446 and non-phosphorylated Thr 451 PKRp do not show any interactions with the bound substrates or inhibitors at the residual level. Stable hydrogen bonds with greater than ten percent of existence were shown in the S2 Table.


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)

Number of intermolecular hydrogen bonds formed by PKR.The plot showing the number of hydrogen bonds between PKR and the interacting proteins in a time dependent manner.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0153680.g002: Number of intermolecular hydrogen bonds formed by PKR.The plot showing the number of hydrogen bonds between PKR and the interacting proteins in a time dependent manner.
Mentions: Hydrogen bonding numbers in protein—protein interactions confers rigidity to the protein structure and specificity of intermolecular interactions. Fig 2 shows the numbers of Hydrogen bonds formed between PKR and proteins in the complex. TAT complex shows an increased number of H-bonds with both forms of PKR. The substrate eIF2α shows a good tendency of H bonding patterns with PKRpp and shows a rapid fall in numbers for PKRp. Inhibitor K3L due to the substrate-mimicking feature exhibits an equal number of H-bonds. The TAT protein interacts with the N lobe terminal α-helices and C lobe αD helices showing an increase number of H bond formation than the other protein complexes. The αG lobe and the N lobe terminal α-helices of the PKRpp protein shows an increased H bond formation than the PKRp protein with the eIF2α which contributes to the increased H bonds numbers of PKRpp-eIF2α complex. The PKRpp-K3L protein complex exhibits H bond formations between phosphorylated Thr 446 and His 47 of the K3L protein. Other protein complexes lack interactions with Thr 446 of the PKR. The double phosphorylated PKRpp-eIF2α, PKRpp-K3L, PKRpp-TAT forms show H-bond formations of phosphorylated Thr with the Arg 54, Arg 56, and Ser57 of eif2α, Lys 45 of K3L; and Lys 28 and Tyr32 of TAT. The phosphorylated Thr 446 and non-phosphorylated Thr 451 PKRp do not show any interactions with the bound substrates or inhibitors at the residual level. Stable hydrogen bonds with greater than ten percent of existence were shown in the S2 Table.

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.