InterPro domain: IPR000961

Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity [ 1 ]:

• Serine/threonine-protein kinases
• Tyrosine-protein kinases
• Dual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)

Protein kinase function is evolutionarily conserved from Escherichia coli to human [ 2 ]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation [ 3 ]. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [ 4 ], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [ 5 ].

The AGC (cAMP-dependent, cGMP-dependent and protein kinase C) protein kinase family embraces a collection of protein kinases that display a high degree of sequence similarity within their respective kinase domains. AGC kinase proteins are characterised by three conserved phosphorylation sites that critically regulate their function. The first one is located in an activation loop in the centre of the kinase domain. The two other phosphorylation sites are located outside the kinase domain in a conserved region on its C-terminal side, the AGC-kinase C-terminal domain. These sites serves as phosphorylation-regulated switches to control both intra- and inter-molecular interactions. Without these priming phosphorylations, the kinases are catalytically inactive [ 6 , 7 , 8 ].

Several structures of the AGC-kinase C-terminal domain have been solved. The first phosphorylation site is located in a turn motif, the second one at the end of the domain in an hydrophobic pocket. In PKB the phosphorylated hydrophobic motif engages a hydrophobic groove within the N-lobe of the kinase domain which orders alpha helices close to the active site [ 9 ].

1. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 241, 42-52
2. The protein kinase complement of the human genome. Science 298, 1912-34
3. Evolution of protein kinase signaling from yeast to man. Trends Biochem. Sci. 27, 514-20
4. High-throughput structural biology in drug discovery: protein kinases. Curr. Pharm. Des. 10, 1069-82
5. Creating chemical diversity to target protein kinases. Comb. Chem. High Throughput Screen. 7, 453-72
6. Regulation of the ABC kinases by phosphorylation: protein kinase C as a paradigm. Biochem. J. 370, 361-71
7. AGC protein kinase phosphorylation and protein kinase C. Biochem. Soc. Trans. 29, 860-3
8. PDK1, the master regulator of AGC kinase signal transduction. Semin. Cell Dev. Biol. 15, 161-70
9. Crystal structure of an activated Akt/protein kinase B ternary complex with GSK3-peptide and AMP-PNP. Nat. Struct. Biol. 9, 940-4