Structure of the Brachydanio rerio Polo-like kinase 1 (Plk1) catalytic domain in complex with an extended inhibitor targeting the adaptive pocket of the enzyme.
Acta Crystallogr Sect F Struct Biol Cryst Commun
; 64(Pt 8): 686-91, 2008 Aug 01.
Article
en En
| MEDLINE
| ID: mdl-18678933
ABSTRACT
Polo-like kinase 1 (Plk1) is a member of the Polo-like kinase family of serine/threonine kinases involved in the regulation of cell-cycle progression and cytokinesis and is an attractive target for the development of anticancer therapeutics. The catalytic domain of this enzyme shares significant primary amino-acid homology and structural similarity with another mitotic kinase, Aurora A. While screening an Aurora A library of ATP-competitive compounds, a urea-containing inhibitor with low affinity for mouse Aurora A but with submicromolar potency for human and zebrafish Plk1 (hPlk1 and zPlk1, respectively) was identified. A crystal structure of the zebrafish Plk1 kinase domain-inhibitor complex reveals that the small molecule occupies the purine pocket and extends past the catalytic lysine into the adaptive region of the active site. Analysis of the structures of this protein-inhibitor complex and of similar small molecules cocrystallized with other kinases facilitates understanding of the specificity of the inhibitor for Plk1 and documents for the first time that Plk1 can accommodate extended ATP-competitive compounds that project toward the adaptive pocket and help the enzyme order its activation segment.
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1
Banco de datos:
MEDLINE
Asunto principal:
Pez Cebra
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Proteínas Proto-Oncogénicas
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Proteínas Serina-Treonina Quinasas
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Proteínas de Ciclo Celular
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Proteínas de Pez Cebra
Límite:
Animals
Idioma:
En
Año:
2008
Tipo del documento:
Article