Kinase ATP binding site

Figure 4 Results of a seeding experiment. The ranks of known p38 MAP kinase inhibitors are shown as horizontal lines in the four diagrams. Inhibitors have been divided into two classes those forming one or two hydrogen bonds to the p38 MAP kinase ATP binding site. The FlexX scoring function preferentially enriches those inhibitors that form two hydrogen bonds. This tendency is less pronounced for the PLP scoring function. The inhibitors with the best predicted affinities are at the top. Data is shown for the top 300 compounds in terms of docking scores.

Figure 3.13. Target family landscape for 26 kinase ATP binding sites, illustrating the differences of several kinase families in chemometric space. A clear distinction between PKA, CDK and MAP kinases is seen in PC 1 and PC 2. With kind permission from Naumann and Matter [10],...

To illustrate the use of the target family landscape for understanding kinase selectivity profiles, Naumann and Matter used a series of 86 2,6,9-substituted purines. These selective CDK inhibitors bind to the kinase ATP binding site [46]. A detailed comparison with experimental selectivity profiles showed good agreement with the chemometric analysis. 

The second structure, adenylate kinase (Figure 4.14b), has two such posi-I tions, one on each side of p strand 1. The connection from strand 1 to strand 12 goes to the right, whereas the connection from the flanking strands 3 and 4 both go to the left. Crevices are formed between p strands 1 and 3 and [between strands 1 and 4. One of these crevices forms part of an AMP-binding [site, and the other crevice forms part of an ATP-binding site that catalyzes the Iformation of ADP from AMP and ATP. 

Most of the PKIs currently in clinical trials are small molecules that compete for the ATP-binding site [3,5]. They prevent the phosphate donor ATP to bind to the protein kinase, and hence the target protein will not become phosphorylated and the perturbed signalling can be terminated. 

Honegger, A., M., J. Dull, T., S. Felder, V. Obberghen, E., F. Bellot, D. Szapary, A. Schmidt, A. Ullrich, and J. Schlessinger. Point mutation at the ATP binding site of EGF receptor abolishes protein-tyrosine kinase activity and alters cellular routing. Cell. 51 199-209.1987. 

The two principal substrates for Raf are MEKl and MEK2, which are dualspecificity kinases that can phosphorylate both serine/threonine and tyrosine residues. MEKl and 2 share 80% sequence identity in the catalytic domain with 100% identity within the ATP binding site. The role of these enzymes in oncogenesis has not been differentiated. As such, the discussions that follow will generally not distinguish them. Interestingly, the enzymes do play different roles in development, as the MEK2 knockout is viable while the MEKl knockout is lethal [20,21]. 

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