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Pharmacol Ther. 2002 Feb-Mar;93(2-3):113-24.

Structural studies with inhibitors of the cell cycle regulatory kinase cyclin-dependent protein kinase 2.

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Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, Rex Richards Building, South Parks Road, OX1 3QU, Oxford, UK.


Components of the cell cycle machinery are frequently altered in cancer. Many of these alterations affect the cyclin-dependent kinases (CDKs) and their regulation. Staurosporine and 7-hydroxystaurosporine (UCN-01) are two natural product kinase inhibitors originally identified as potent protein kinase C inhibitors. Staurosporine is non-selective and too toxic for use in therapy, but UCN-01 shows greater selectivity, and is in clinical trials. We have determined the crystal structures of staurosporine bound to monomeric CDK2 and UCN-01 bound to active phospho-CDK2/cyclin A. Both compounds mimic the hydrogen bonds made by the adenine moiety of ATP, and both exploit the non-polar nature of the adenine-binding site. In the complex with UCN-01, a hydrogen-bonded water molecule is incorporated into the non-polar cavity, which provides a partial polar character in the environment of the 7-hydroxyl group. Comparison of the ATP-binding site of CDK2 with that of other kinases reveals that in Chk1 kinase, a major target for UCN-01 in the cell, one of the surrounding residues, Ala144 in CDK2, is a serine in Chk1, thus providing a possible explanation for the effectiveness of UCN-01 against this kinase. For cells to exit mitosis, the CDKs must be completely inactivated, firstly by the ubiquintin-mediated destruction of the cyclins, followed by dephosphorylation of phospho-Thr160 (in CDK2) catalysed by the kinase-associated phosphatase and protein phosphatase 2C. We describe the structure of phospho-CDK2 in complex with kinase-associated phosphatase, and discuss the substrate recognition promoted by interactions that are remote from the catalytic site.

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