6D3L

Crystal structure of unphosphorylated human PKR

Summary for 6D3L

• Entry DOI: 10.2210/pdb6d3l/pdb
• Descriptor: Interferon-induced, double-stranded RNA-activated protein kinase (1 entity in total)
• Functional Keywords: unphosphorylated, kinase, activation loop swapping, apo, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 37445.77

Authors

Erlandsen, H.,Mayo, C.,Robinson, V.L.,Cole, J.L. (deposition date: 2018-04-16, release date: 2019-07-10, Last modification date: 2023-10-04)

Primary citation

Mayo, C.B.,Erlandsen, H.,Mouser, D.J.,Feinstein, A.G.,Robinson, V.L.,May, E.R.,Cole, J.L.
Structural Basis of Protein Kinase R Autophosphorylation.
Biochemistry, 58:2967-2977, 2019

PubMed Abstract: 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 eIF2α.

PubMed: 31246429
DOI: 10.1021/acs.biochem.9b00161

Experimental method

X-RAY DIFFRACTION (3.1 Å)