Molecular models of cyclin-dependent kinase 1 complexed with inhibitors.
Roscovitine and flavopiridol have been shown to potently inhibit cyclin-dependent kinase 1 and 2 (CDK1 and 2). The structures of CDK2 complexed with roscovitine and deschoroflavopiridol have been reported, however no crystallographic structure is available for complexes of CDK1 with inhibitors. The present work describes two molecular models for the binary complexes CDK1:roscovitine and CDK1:flavopiridol. These structural models indicate that both inhibitors strongly bind to the ATP-binding pocket of CDK1 and structural comparison of the CDK complexes correlates the structures with differences in inhibition of these CDKs by flavopiridol and roscovitine. This article explains the structural basis for the observed differences in activity of these inhibitors.
Canduri
Fernanda
F
Departamento de Física, UNESP, São José do Rio Preto, SP. 15054-000, Brazil; Programa de Pós-Graduação em Biofísica Molecular-UNESP, São José do Rio Preto, SP 15054-000, Brazil. canduri@df.ibilce.unesp.br
Uchoa
Hugo Brandão
HB
de Azevedo
Walter Filgueira
WF
D000595:Amino Acid Sequence; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D042846:CDC2-CDC28 Kinases / Q000737:chemistry; D051357:Cyclin-Dependent Kinase 2; D015195:Drug Design; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010880:Piperidines / Q000494:pharmacology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011687:Purines / Q000494:pharmacology; D000077546:Roscovitine; D017386:Sequence Homology, Amino Acid
D005419:Flavonoids; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; C077990:alvocidib; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2