Kinase ATP binding

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 molecular mechanism behind imatinib resistance mirrors its molecular mechanism of action. Bcr-Abl gene duplication as well as transcriptional mechanisms leading to increases in Bcr-Abl transcript levels can lead to imatinib resistance. Thus, the Bcr-Abl inhibition exerts selective pressure on CML tumors to increase Bcr-Abl signaling, which is manifest by upregulation of Bcr-Abl messenger RNA. Another common mechanism of resistance is the mutation of the Bcr-Abl kinase ATP-binding pocket in which imatinib binds [11]. The mutation in the ATP-binding pocket produces a Bcr-Abl protein kinase, which can carry out ATP-dependent substrate phosphorylation but... 

The catalytic subunit of cAPK contains two domains connected by a peptide linker. ATP binds in a deep cleft between the two domains. Presently, crystal structures showed cAPK in three different conformations, (1) in a closed conformation in the ternary complex with ATP or other tight-binding ligands and a peptide inhibitor PKI(5-24), (2) in an intermediate conformation in the binary complex with adenosine, and (3) in an open conformation in the binary complex of mammalian cAPK with PKI(5-24). Fig.l shows a superposition of the three protein kinase configurations to visualize the type of conformational movement. 

Left side of Fig. 4 shows a ribbon model of the catalytic (C-) subunit of the mammalian cAMP-dependent protein kinase. This was the first protein kinase whose structure was determined [35]. Figure 4 includes also a ribbon model of the peptide substrate, and ATP (stick representation) with two manganese ions (CPK representation). All kinetic evidence is consistent with a preferred ordered mechanism of catalysis with ATP binding proceeding substrate binding. 

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. 

The most extensive development of pharmacological inhibitors of MAPK cascades members has been for p38 (Table 1) [3]. Small-molecule inhibitors have been developed for two p38 isoforms (a and (3). Pyridinyl imidazole compounds have been known to block inflammation since the early 1970s. Structural analyses have revealed that p38 kinase inhibitors binds to the ATP-binding pocket of p38 thereby acting as competitive inhibitors. The p38 kinase inhibitor SB202190 is able to bind both the low-activity nonphosphorylated... 

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. 

The mechanism of action proposed is based on a direct binding to the channel and the following partial block of the ATP-binding pocket of CFTR (French et al., 1997), a mechanism similar to that used by genistein to inhibit the activity of other ATP-utilizing enzymes such as protein kinases and topoisomerase II (Polkowski and Mazurek, 2000 and refs therein). The selection of flavonoid compounds or the development of synthetic drugs reasonably selective for CFTR activation might be an area for future clinical trials. 

The abundance of structural information has led to a significant increase in the use of structure-based methods both to identify and to optimise inhibitors of protein kinases. The focus to date has centred upon small molecule ATP-competitive inhibitors and there are numerous examples of protein-ligand complexes available to guide design strategies. ATP binds in the cleft formed between the N- and C-terminal lobes of the protein kinase, forming several key interactions conserved across the protein kinase family. The adenine moiety lies in a hydrophobic region between the jS-sheet structure of subdomains I and II and residues from subdomains V and VIb. A... 

Gleevec ) is a tyrosine kinase inhibitor used as first-line therapy in the majority of patients with CML. As a potent tyrosine kinase inhibitor, imatinib inhibits phosphorylation of various proteins involved in cell proliferation. Imatinib works by binding to the ATP-binding pocket of BCR-ABL.7 The drug induces complete hematologic responses in more than 95% of patients and complete cytogenetic responses in about 80% of patients in chronic phase.8 Most patients have traces of the disease when measured by RT-PCR and are not cured of their disease. 

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