This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.
Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.
1nvs
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: UCM]] | [[Category: UCM]] | ||
[[Category: chk1-sb218078 complex]] | [[Category: chk1-sb218078 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 14:10:41 2008'' |
Revision as of 12:10, 21 February 2008
|
The Complex Structure Of Checkpoint Kinase Chk1/SB218078
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
1NVS 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 14:10:41 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 | UCM | Chk1-sb218078 complex
