RESUMO
The crystal structure of human replication and transcription cofactor PC4CTD reveals a dimer with two single-stranded (ss)DNA binding channels running in opposite directions to each other. This arrangement suggests a role in establishment or maintenance of melted DNA at promoters or origins of replication.
Assuntos
DNA de Cadeia Simples/metabolismo , Proteínas Repressoras , Transativadores/química , Sequência de Aminoácidos , Sítios de Ligação , Cristalografia por Raios X , Dimerização , Humanos , Proteínas Imediatamente Precoces , Proteínas de Membrana , Modelos Moleculares , Dados de Sequência MolecularRESUMO
The central role of cyclin-dependent kinases (CDKs) in cell cycle regulation makes them a promising target for discovering small inhibitory molecules that can modify the degree of cell proliferation. The three-dimensional structure of CDK2 provides a structural foundation for understanding the mechanisms of activation and inhibition of CDK2 and for the discovery of inhibitors. In this article five structures of human CDK2 are summarised: apoprotein, ATP complex, olomoucine complex, isopentenyladenine complex, and des-chloro-flavopiridol complex.
Assuntos
Quinases relacionadas a CDC2 e CDC28 , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/química , Adenina/análogos & derivados , Adenina/farmacologia , Trifosfato de Adenosina/química , Animais , Sítios de Ligação , Ciclo Celular , Cristalografia por Raios X , Quinase 2 Dependente de Ciclina , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Flavonoides/farmacologia , Humanos , Isopenteniladenosina , Cinetina , Ligantes , Substâncias Macromoleculares , Modelos Moleculares , Piperidinas/farmacologia , Conformação Proteica , Purinas/farmacologia , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/químicaRESUMO
Cyclin-dependent kinases (CDKs) are conserved regulators of the eukaryotic cell cycle with different isoforms controlling specific phases of the cell cycle. Mitogenic or growth inhibitory signals are mediated, respectively, by activation or inhibition of CDKs which phosphorylate proteins associated with the cell cycle. The central role of CDKs in cell cycle regulation makes them a potential new target for inhibitory molecules with anti-proliferative and/or anti-neoplastic effects. We describe the crystal structures of the complexes of CDK2 with a weakly specific CDK inhibitor, N6-(delta 2-isopentenyl)adenine, and a strongly specific inhibitor, olomoucine. Both inhibitors are adenine derivatives and bind in the adenine binding pocket of CDK2, but in an unexpected and different orientation from the adenine of the authentic ligand ATP. The N6-benzyl substituent in olomoucine binds outside the conserved binding pocket and is most likely responsible for its specificity. The structural information from the CDK2-olomoucine complex will be useful in directing the search for the next generation inhibitors with improved properties.