CSNK1G3: Human Casein Kinase I gamma 3
PDB Code: 2CHL
CKI represents a unique group of serine/threonine protein kinases that is ubiquitously expressed in eukaryotic organisms. Seven mammalian CKI isoforms (α, β, γ1, γ2, γ3, δ and ε) and various splice variants have been identified to date. CKI family members contain a highly conserved N-terminal catalytic domain coupled to a variable C-terminal region that ranges in size from 40 to 180 amino acids. Casein kinases have been described to act as monomeric, constitutively active enzymes.
CSNK1G3 is widely expressed with high RNA levels detected in testis and levels found in brain, heart, liver, kidney and muscle
The characterization of the substrate specificity of CKI isoforms initially led to the identification of the canonical consensus sequence S/T(P)-X 1-2 -S/T, indicating that modification of serine or threonine residues by CKI requires the preceding phosphorylation of amino acid residues N-terminal of the target site. This requirement of a priming phosphorylation by another kinase restricted CKI to a function in the hierarchical phosphorylation of substrates. However, further studies revealed that a cluster of acidic amino acids N-terminal of the target serine/ threonine and an acidic amino acid in position n-3 could substitute for the phosphoamino acid efficiently. This non-canonical motif consisting of the sequence SLS has been shown to be recognized by CKI in combination with a cluster of acidic amino acid residues C-terminal of the phosphoacceptor site. The CKI substrates NF-AT and β-catenin exhibit such motifs, but phosphorylation of this non-canonical motif is 15-25 fold less efficient compared to the motif primed by a phosphoamino acid.
siRNAs targeting of CNK1G3 significantly enhances cell killing by A-443654 , an inhibitor of the protein kinase Akt. Small molecules targeting CSNK1G3 in addition to Akt may thus exhibit increased efficacy and have the potential for improved therapeutic index.
We have structure determined human CSNK1G3 in complex with an inhibitor of the triazolo-diamine class that has been described as a cell-permeable compound that displays anti-proliferative properties in various human cancer cells (IC50 = 20 nM, 35 nM and 92 nM in HCT-116, HeLa, and A375 cells, respectively). This inhibitor acts as a highly potent, ATP-competitive inhibitor of Cdk1/cyclin B and Cdk2/cyclin A (IC50 = 600 pM and 500 pM, respectively).
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