Sequence and structural analysis of kinase ATP pocket residues

Protein kinases represent one of the largest known families of enzymes. Most kinases bind ATP and most synthetic kinase inhibitors are ATP-competitive, which makes selectivity a potential problem. However, despite the high sequence similarity in the ATP binding pocket, several groups including ours have been able to develop highly potent and selective ATP-competitive inhibitors. To systematically aid the design of specific inhibitors in our protein kinase projects, we aligned all known three-dimensional structures and all known sequences of human protein kinases. We identified a set of 38 residues that make up the ATP pocket and analyzed the variability among these residues. The most variable residues in the ATP pocket are targeted to design specificity into inhibitors in our various kinase projects.