Protein kinases folding

Protein Folding Problem Protein Kinase Protein Kinase A Protein Kinase C Protein Kinase Inhibitors Protein Phosphatases Protein Sorting... 

Fig. 6. Distribution of the most common folds in selected bacterial, archaeal, and eukaryotic proteomes. The vertical axis shows the fraction of all predicted folds in the respective proteome. Fold name abbreviations FAD/NAD, FAD/NAD(P)-binding Rossman-like domains TIM, TIM-barrel domains SAM-MTR, S-adenosylmethionine-dependent methyltransferases PK, serine-threonine protein kinases PP-Loop, ATP pyrophosphatases. mge, Mycoplasma genitalium rpr, Rickettsiaprowazekii hh x, Borrelia burgdorferi ctr, Chlamydia trachomatis hpy, Helicobacter pylori tma, Thermotoga maritima ssp, Synechocystis sp. mtu, Mycobacterium tuberculosis eco, Escherichia coli mja, Methanococcus jannaschii pho, Pyrococcus horikoshii see, Saccharomyces cerevisiae, cel, Caenorhabditis elegans.

A more detailed breakdown of the fold abundance by individual genomes shows the same trends, as well as a number of unique features (Fig. 6, see color insert). The latter include, for example, the marked overrepresentation of Rossmann-fold domains in Mycobacterium, flavo-doxins in Synechocystis and methyltransferases in Helicobacter. Furthermore, the differences in fold distribution between the multicellular eukaryote Caenorhabditis elegans and the unicellular yeast become readily apparent. In the nematode, the protein kinases are the most common fold, with the P-loops relegated to the second position in contrast, the yeast distribution is more similar to that seen in prokaryotes (Fig. 6). 

In addition to UCN-01 and other staurosporine or maleimide derivatives (e.g., compounds 17 and 18 Fig. 4) [102,103,105-107], PDKl kinase activity is inhibited by aminopyrimidines. A representative example of this compound class is BX-320 (compound 19, Fig. 4), a PDKl inhibitor (IC50 = 30 nM) that displays good selectivity over protein kinase A (PKA, 35-fold) [108]. BX-320 blocks the growth in soft agar of a wide range of tumor cell lines (IC50 = 0.093 to 1.32 xM), and shows efficacy in a metastasis mouse model (200 mg/kg bid). 

There are many other protein kinases that do not show any close relationship to these subfamilies. These include protein kinases with two-fold specificity, in that they can phosphorylate Ser/Thr and also Tyr residues. An example of a protein kinase with twofold specificity is the MAP kinase kinase (see Chapter 10). 

The MEK proteins are a special class of protein kinases since they have two-fold specificity with respect to the nature of the acceptor amino acid at the phosphorylation site of the protein substrate (review Dhanasekaran and Reddy, 1998). Tire MEKs activate... 

Phosphorylation of the CycA-CDC2 complex at ThrlhO leads to a near 300-fold increase in protein kinase activity. Thrl60 of CDK2 hes in the activation segment (also known as the T loop) that blocks the access to the substrate binding site in the inactive... 

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