1nvr
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The Complex Structure Of Checkpoint Kinase Chk1/Staurosporine
OverviewOverview
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 StructureAbout this Structure
1NVR is a Single protein structure of sequence from Homo sapiens with SO4 and STU as ligands. Full crystallographic information is available from OCA.
ReferenceReference
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
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