2rku
From Proteopedia
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==Overview== | ==Overview== | ||
| - | Polo-like kinase 1 is an important regulator of cell cycle progression | + | 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. |
==About this Structure== | ==About this Structure== | ||
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[[Category: Polo kinase]] | [[Category: Polo kinase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Ding, Y | + | [[Category: Ding, Y H.]] |
[[Category: Kohls, D.]] | [[Category: Kohls, D.]] | ||
[[Category: Kothe, M.]] | [[Category: Kothe, M.]] | ||
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[[Category: transferase]] | [[Category: transferase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:48:09 2008'' |
Revision as of 16:48, 21 February 2008
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Structure of PLK1 in complex with BI2536
Overview
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.
About this Structure
2RKU is a Single protein structure of sequence from Homo sapiens with , , , and as ligands. Active as Polo kinase, with EC number 2.7.11.21 Known structural/functional Sites: , , , , , and . Full crystallographic information is available from OCA.
Reference
Selectivity-determining residues in Plk1., Kothe M, Kohls D, Low S, Coli R, Rennie GR, Feru F, Kuhn C, Ding YH, Chem Biol Drug Des. 2007 Dec;70(6):540-6. Epub 2007 Nov 13. PMID:18005335
Page seeded by OCA on Thu Feb 21 18:48:09 2008
Categories: Homo sapiens | Polo kinase | Single protein | Ding, Y H. | Kohls, D. | Kothe, M. | Low, S. | R78 | SRT | TAR | TLA | ZN | Atp-binding | Kinase | Nucleotide-binding | Nucleus | Phosphorylation | Polo-like kinase | Selectivity residues | Serine/threonine-protein kinase | Structure based drug design | Structure of plk1 | Transferase
