title: Crystal structure of human cyclin-dependent kinase 2 in complex with the adenine-derived inhibitor H717.
abstract: Cyclin-dependent kinases (CDKs) are regulatory proteins of the eukaryotic cell cycle. They act after association with different cyclins, the concentrations of which vary throughout the progression of the cell cycle. As central mediators of cell growth, CDKs are potential targets for inhibitory molecules that would allow disruption of the cell cycle in order to evoke an antiproliferative effect and may therefore be useful as cancer therapeutics. We synthesized several inhibitory 2,6,9-trisubstituted purine derivatives and solved the crystal structure of one of these compounds, H717, in complex with human CDK2 at 2.6 A resolution. The orientation of the C2-p-diaminocyclohexyl portion of the inhibitor is strikingly different from those of similar moieties in other related inhibitor complexes. The N9-cyclopentyl ring fully occupies a space in the enzyme which is otherwise empty, while the C6-N-aminobenzyl substituent points out of the ATP-binding site. The structure provides a basis for the further development of more potent inhibitory drugs.
authors.affiliation: Department of Chemistry and Lawrence Berkeley National Laboratory, University of California, Berkeley, California 94720, USA. dreyer@biozentrum.uni.wuerzburg.de
authors.forename: M K
authors.initials: MK
authors.lastname: Dreyer
authors.forename: D R
authors.initials: DR
authors.lastname: Borcherding
authors.forename: J A
authors.initials: JA
authors.lastname: Dumont
authors.forename: N P
authors.initials: NP
authors.lastname: Peet
authors.forename: J T
authors.initials: JT
authors.lastname: Tsay
authors.forename: P S
authors.initials: PS
authors.lastname: Wright
authors.forename: A J
authors.initials: AJ
authors.lastname: Bitonti
authors.forename: J
authors.initials: J
authors.lastname: Shen
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000737:chemistry*; D042846:CDC2-CDC28 Kinases; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; C421623:H717 compound; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D000225:Adenine