1HCL

HUMAN CYCLIN-DEPENDENT KINASE 2

Summary for 1HCL

• Entry DOI: 10.2210/pdb1hcl/pdb
• Related: 1HCK
• Descriptor: HUMAN CYCLIN-DEPENDENT KINASE 2 (2 entities in total)
• Functional Keywords: transferase, serine/threonine protein kinase, atp-binding, cell cycle, cell division, mitosis, phosphorylation, protein kinase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 33976.49

Authors

Schulze-Gahmen, U.,De Bondt, H.L.,Kim, S.-H. (deposition date: 1996-06-03, release date: 1996-12-07, Last modification date: 2024-02-07)

Primary citation

Schulze-Gahmen, U.,De Bondt, H.L.,Kim, S.H.
High-resolution crystal structures of human cyclin-dependent kinase 2 with and without ATP: bound waters and natural ligand as guides for inhibitor design.
J.Med.Chem., 39:4540-4546, 1996

PubMed Abstract: 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.

PubMed: 8917641
DOI: 10.1021/jm960402a

Experimental method

X-RAY DIFFRACTION (1.8 Å)