6d3k | pdb_00006d3k

Crystal structure of unphosphorylated human PKR kinase domain in complex with ADP

spinqualitylabelsall models 6d3k, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6d3k is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.6Å Ligands: ADP, MG, PO4, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function E2AK2_HUMAN Following activation by double-stranded RNA in the presence of ATP, the kinase becomes autophosphorylated and can catalyze the phosphorylation of the translation initiation factor EIF2S1, which leads to an inhibition of the initiation of protein synthesis. Double-stranded RNA is generated during the course of a viral infection. In addition to serine/threonine-protein kinase activity, also has tyrosine-protein kinase activity: phosphorylates CDK1 upon DNA damage. CDK1 phosphorylation triggers CDK1 polyubiquitination and subsequent proteolysis, thus leading to G2 arrest. Publication Abstract from PubMed The RNA-activated protein kinase, PKR, is a key mediator of the innate immunity response to viral infection. Viral double-stranded RNAs induce PKR dimerization and autophosphorylation. The PKR kinase domain forms a back-to-back dimer. However, intermolecular ( trans) autophosphorylation is not feasible in this arrangement. We have obtained PKR kinase structures that resolves this dilemma. The kinase protomers interact via the known back-to-back interface as well as a front-to-front interface that is formed by exchange of activation segments. Mutational analysis of the front-to-front interface support a functional role in PKR activation. Molecular dynamics simulations reveal that the activation segment is highly dynamic in the front-to-front dimer and can adopt conformations conducive to phosphoryl transfer. We propose a mechanism where back-to-back dimerization induces a conformational change that activates PKR to phosphorylate a "substrate" kinase docked in a front-to-front geometry. This mechanism may be relevant to related kinases that phosphorylate the eukaryotic initiation factor eIF2alpha. Structural Basis of Protein Kinase R Autophosphorylation.,Mayo CB, Erlandsen H, Mouser DJ, Feinstein AG, Robinson VL, May ER, Cole JL Biochemistry. 2019 Jul 9;58(27):2967-2977. doi: 10.1021/acs.biochem.9b00161. Epub, 2019 Jun 27. PMID:31246429 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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