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.
Computational Sciences, Nerviano Medical Science, Viale Pasteur 10, 20014 Nerviano (MI), Italy. anna.vulpetti@nervianoms.com
Anna
A
Vulpetti
Roberta
R
Bosotti
D000255:Adenosine Triphosphate / Q000737:chemistry*; D000595:Amino Acid Sequence; D001665:Binding Sites; D015195:Drug Design; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry*; D016415:Sequence Alignment
D047908:Intracellular Signaling Peptides and Proteins; C015482:protein kinase modulator; D000255:Adenosine Triphosphate; D011494:Protein Kinases