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.

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.

DOI: 10.1107/S1744309108019623

Cite this paper

@article{Elling2008StructureOT, title={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.}, author={Robert A. Elling and Raymond V. Fucini and Emily J. Hanan and Kenneth J. Barr and Jiang Zhu and Kumar Paulvannan and Wenjin Yang and Michael J. Romanowski}, journal={Acta crystallographica. Section F, Structural biology and crystallization communications}, year={2008}, volume={64 Pt 8}, pages={686-91} }