2RKU

Structure of PLK1 in complex with BI2536

2RKU の概要

• エントリーDOI: 10.2210/pdb2rku/pdb
• 分子名称: Serine/threonine-protein kinase PLK1, ZINC ION, 4-{[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide, ... (7 entities in total)
• 機能のキーワード: structure of plk1, selectivity residues, kinase, polo-like kinase, structure based drug design, atp-binding, nucleotide-binding, nucleus, phosphorylation, serine/threonine-protein kinase, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus: P53350
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35160.96

構造登録者

Ding, Y.-H.,Kothe, M.,Kohls, D.,Low, S. (登録日: 2007-10-17, 公開日: 2008-02-05, 最終更新日: 2024-02-21)

主引用文献

Kothe, M.,Kohls, D.,Low, S.,Coli, R.,Rennie, G.R.,Feru, F.,Kuhn, C.,Ding, Y.-H.
Selectivity-determining residues in Plk1.
Chem.Biol.Drug Des., 70:540-546, 2007

PubMed Abstract: Polo-like kinase 1 is an important regulator of cell cycle progression whose over-expression is often associated with oncogenesis. Polo-like kinase 1 hence represents an attractive target for cancer intervention. BI 2536 (Boehringer Ingelheim, Ingelheim, Germany), a Polo-like kinase 1 inhibitor currently in clinical trials, exhibits nanomolar potency against Polo-like kinase isoforms and high selectivity against other kinases. We have previously published the crystal structures of the Polo-like kinase 1 domain in complex with AMPPNP and an Aurora A inhibitor. In this work, we present the co-crystal structure of Polo-like kinase 1 with BI 2536. The structure, in combination with selectivity data for BI 2536 and related compounds, illustrates important features for potency and selectivity. In particular, we show that the methoxy group of BI 2536 is an important specificity determinant against non-Polo-like kinases by taking advantage of a small pocket generated by Leu 132 in the hinge region of Polo-like kinase 1. The work presented here provides a framework for structure-based drug design of Polo-like kinase 1-specific inhibitors.

PubMed: 18005335
DOI: 10.1111/j.1747-0285.2007.00594.x

実験手法

X-RAY DIFFRACTION (1.95 Å)