3DB6

Crystal structure of an activated (Thr->Asp) Polo-like kinase 1 (Plk1) catalytic domain in complex with Compound 902

Summary for 3DB6

• Entry DOI: 10.2210/pdb3db6/pdb
• Related: 3d5u 3d5v 3d5w 3d5x
• Descriptor: Polo-like kinase 1, 1-[5-methyl-2-(trifluoromethyl)furan-3-yl]-3-[(2Z)-5-(2-{[6-(1H-1,2,4-triazol-3-ylamino)pyrimidin-4-yl]amino}ethyl)-1,3-thiazol-2(3H)-ylidene]urea (3 entities in total)
• Functional Keywords: polo-like kinase 1, plk1, catalytic domain, small-molecule inhibitor, kinase, transferase
• Biological source: Danio rerio (zebra fish)
• Total number of polymer chains: 1
• Total formula weight: 34936.57

Authors

Elling, R.A.,Fucini, R.V.,Zhu, J.,Barr, K.J.,Romanowski, M.J. (deposition date: 2008-05-30, release date: 2008-08-19, Last modification date: 2023-11-29)

Primary citation

Elling, R.A.,Fucini, R.V.,Hanan, E.J.,Barr, K.J.,Zhu, J.,Paulvannan, K.,Yang, W.,Romanowski, M.J.
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, 64:686-691, 2008

PubMed 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.

PubMed: 18678933
DOI: 10.1107/S1744309108019623

Experimental method

X-RAY DIFFRACTION (2.85 Å)