1hck
|
HUMAN CYCLIN-DEPENDENT KINASE 2
OverviewOverview
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.
About this StructureAbout this Structure
1HCK is a Single protein structure of sequence from Homo sapiens with MG and ATP as ligands. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Full crystallographic information is available from OCA.
ReferenceReference
High-resolution crystal structures of human cyclin-dependent kinase 2 with and without ATP: bound waters and natural ligand as guides for inhibitor design., Schulze-Gahmen U, De Bondt HL, Kim SH, J Med Chem. 1996 Nov 8;39(23):4540-6. PMID:8917641
Page seeded by OCA on Mon Nov 12 17:15:48 2007