PUBLICATION
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
- Authors
- Elling, R.A., Fucini, R.V., Hanan, E.J., Barr, K.J., Zhu, J., Paulvannan, K., Yang, W., and Romanowski, M.J.
- ID
- ZDB-PUB-080825-18
- Date
- 2008
- Source
- Acta crystallographica. Section F, Structural biology and crystallization communications 64(Pt 8): 686-691 (Journal)
- Registered Authors
- Keywords
- Polo-like kinase 1, small-molecule inhibitors, zebrafish
- MeSH Terms
-
- Models, Molecular
- Catalytic Domain
- Cell Cycle Proteins/antagonists & inhibitors
- Cell Cycle Proteins/chemistry*
- Cell Cycle Proteins/genetics
- Crystallography, X-Ray
- Animals
- Substrate Specificity
- Protein Conformation
- Protein Serine-Threonine Kinases/antagonists & inhibitors
- Protein Serine-Threonine Kinases/chemistry*
- Protein Serine-Threonine Kinases/genetics
- Base Sequence
- Proto-Oncogene Proteins/antagonists & inhibitors
- Proto-Oncogene Proteins/chemistry*
- Proto-Oncogene Proteins/genetics
- Mutagenesis, Site-Directed
- DNA Primers
- Zebrafish/metabolism*
- Zebrafish Proteins/antagonists & inhibitors
- Zebrafish Proteins/chemistry*
- Zebrafish Proteins/genetics
- PubMed
- 18678933 Full text @ Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun.
Citation
Elling, R.A., Fucini, R.V., Hanan, E.J., Barr, K.J., Zhu, J., Paulvannan, K., Yang, W., and Romanowski, M.J. (2008) 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 crystallographica. Section F, Structural biology and crystallization communications. 64(Pt 8):686-691.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping