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.
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.
Elling
Robert A
RA
Department of Structural Biology, Sunesis Pharmaceuticals Inc., USA.
Fucini
Raymond V
RV
Hanan
Emily J
EJ
Barr
Kenneth J
KJ
Zhu
Jiang
J
Paulvannan
Kumar
K
Yang
Wenjin
W
Romanowski
Michael J
MJ
D000818:Animals; D001483:Base Sequence; D020134:Catalytic Domain; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D018360:Crystallography, X-Ray; D017931:DNA Primers; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D013379:Substrate Specificity; D015027:Zebrafish / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D017931:DNA Primers; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D029961:Zebrafish Proteins; D000097869:Polo-Like Kinase 1