Kinase cocrystallization

The first section describes the structure of kinases in general, the specific domains as well as the activation mechanism, and is followed by a section on the different kinase inhibition principles. In the next section, a detailed description of the structural features of all kinase inhibitors currently cocrystallized with their target kinase is given. Finally, some structural features that determine the selectivity of several kinase inhibitors are addressed. 

Isolated in 1977 from the bacterium Streptomyces staurosporeus, staurosporine (3) is a natural product that inhibits most protein kinases at low nanomolar concentrations [23]. Through small-molecule/protein complex cocrystallization, it was shown that staurosporine binds tightly to the adenosine binding pocket ofthe catalytic subunit of the cAMP-dependent protein kinase. Chelerythrine (4) was identified as an inhibitor of Bcl-XL-Bak BH3 peptide binding vdth an IC50 of 1.5 p,M, and also displaced Bax from Bcl-XL [24]. Chelidonine (S) is another example of an alkaloid natural product that inhibits the taxol-mediated polymerization of tubulin in the micromolar range ( 24.0 p,M). 

Figure4.10 Superimposition of protein kinase A structures Istc (green) and IqSu (red) together with their cocrystallized ligands staurosporine (blue) and (S)-2-methyl-l-[(4-methyl-5-isoquinoline) sulfonyl]- homopipera-...

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