1nvq
From Proteopedia
| Line 4: | Line 4: | ||
==Overview== | ==Overview== | ||
| - | Chk1 is a serine-threonine kinase that plays an important role in the DNA | + | Chk1 is a serine-threonine kinase that plays an important role in the DNA damage response, including G(2)/M cell cycle control. UCN-01 (7-hydroxystaurosporine), currently in clinical trials, has recently been shown to be a potent Chk1 inhibitor that abrogates the G(2)/M checkpoint induced by DNA-damaging agents. To understand the structural basis of Chk1 inhibition by UCN-01, we determined the crystal structure of the Chk1 kinase domain in complex with UCN-01. Chk1 structures with staurosporine and its analog SB-218078 were also determined. All three compounds bind in the ATP-binding pocket of Chk1, producing only slight changes in the protein conformation. Selectivity of UCN-01 toward Chk1 over cyclin-dependent kinases can be explained by the presence of a hydroxyl group in the lactam moiety interacting with the ATP-binding pocket. Hydrophobic interactions and hydrogen-bonding interactions were observed in the structures between UCN-01 and the Chk1 kinase domain. The high structural complementarity of these interactions is consistent with the potency and selectivity of UCN-01. |
==About this Structure== | ==About this Structure== | ||
| Line 13: | Line 13: | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Bower, M | + | [[Category: Bower, M J.]] |
| - | [[Category: Concha, N | + | [[Category: Concha, N O.]] |
| - | [[Category: Davis, S | + | [[Category: Davis, S T.]] |
| - | [[Category: Green, S | + | [[Category: Green, S M.]] |
| - | [[Category: Johanson, K | + | [[Category: Johanson, K O.]] |
| - | [[Category: McDevitt, P | + | [[Category: McDevitt, P J.]] |
[[Category: Zhao, B.]] | [[Category: Zhao, B.]] | ||
[[Category: Zhao, H.]] | [[Category: Zhao, H.]] | ||
| - | [[Category: Zhou, B | + | [[Category: Zhou, B B.]] |
[[Category: SO4]] | [[Category: SO4]] | ||
[[Category: UCN]] | [[Category: UCN]] | ||
[[Category: chk1-ucn-01 complex]] | [[Category: chk1-ucn-01 complex]] | ||
| - | ''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 14:10:36 2008'' |
Revision as of 12:10, 21 February 2008
|
The Complex Structure Of Checkpoint Kinase Chk1/UCN-01
Overview
Chk1 is a serine-threonine kinase that plays an important role in the DNA damage response, including G(2)/M cell cycle control. UCN-01 (7-hydroxystaurosporine), currently in clinical trials, has recently been shown to be a potent Chk1 inhibitor that abrogates the G(2)/M checkpoint induced by DNA-damaging agents. To understand the structural basis of Chk1 inhibition by UCN-01, we determined the crystal structure of the Chk1 kinase domain in complex with UCN-01. Chk1 structures with staurosporine and its analog SB-218078 were also determined. All three compounds bind in the ATP-binding pocket of Chk1, producing only slight changes in the protein conformation. Selectivity of UCN-01 toward Chk1 over cyclin-dependent kinases can be explained by the presence of a hydroxyl group in the lactam moiety interacting with the ATP-binding pocket. Hydrophobic interactions and hydrogen-bonding interactions were observed in the structures between UCN-01 and the Chk1 kinase domain. The high structural complementarity of these interactions is consistent with the potency and selectivity of UCN-01.
About this Structure
1NVQ is a Single protein structure of sequence from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.
Reference
Structural basis for Chk1 inhibition by UCN-01., Zhao B, Bower MJ, McDevitt PJ, Zhao H, Davis ST, Johanson KO, Green SM, Concha NO, Zhou BB, J Biol Chem. 2002 Nov 29;277(48):46609-15. Epub 2002 Sep 19. PMID:12244092
Page seeded by OCA on Thu Feb 21 14:10:36 2008
Categories: Homo sapiens | Single protein | Bower, M J. | Concha, N O. | Davis, S T. | Green, S M. | Johanson, K O. | McDevitt, P J. | Zhao, B. | Zhao, H. | Zhou, B B. | SO4 | UCN | Chk1-ucn-01 complex
