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Title
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High-resolution crystal structures of human cyclin-dependent kinase 2 with and without ATP: bound waters and natural ligand as guides for inhibitor design.
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Authors
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U.Schulze-Gahmen,
H.L.De Bondt,
S.H.Kim.
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Ref.
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J Med Chem, 1996,
39,
4540-4546.
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PubMed id
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Abstract
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Inhibition of the cell cycle is widely considered as a new approach toward
treatment for diseases caused by unregulated cell proliferation, including
cancer. Since cyclin-dependent kinases (CDKs) are key enzymes of cell cycle
control, they are promissing targets for the design and discovery of drugs with
antiproliferative activity. The detailed structural analysis of CDK2 can provide
valuable information for the design of new ligands that can bind in the ATP
binding pocket and inhibit CDK2 activity. For this objective, the crystal
structures of human CDK2 apoenzyme and its ATP complex were refined to 1.8 and
1.9 A, respectively. The high-resolution refinement reveals 12 ordered water
molecules in the ATP binding pocket of the apoenzyme and five ordered waters in
that of the ATP complex. Despite a large number of hydrogen bonds between
ATP-phosphates and CDK2, binding studies of cyclic AMP-dependent protein kinase
with ATP analogues show that the triphosphate moiety contributes little and the
adenine ring is most important for binding affinity. Our analysis of CDK2
structural data, hydration of residues in the binding pocket of the apoenzyme,
flexibility of the ligand, and structural differences between the apoenzyme and
CDK2-ATP complex provide an explanation for the results of earlier binding
studies with ATP analogues and a basis for future inhibitor design.
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