1nvr: Difference between revisions

Revision as of 15:10, 21 February 2008

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 and 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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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

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 '''The Complex Structure Of Checkpoint Kinase Chk1/Staurosporine'''<br />
 ==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.
+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==
-NVR is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SO4 and STU as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1NVR OCA].
+NVR is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=STU:'>STU</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1NVR OCA].
 ==Reference==
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 [[Category: Homo sapiens]]
 [[Category: Single protein]]
-[[Category: Bower, M.J.]]
+[[Category: Bower, M J.]]
-[[Category: Concha, N.O.]]
+[[Category: Concha, N O.]]
-[[Category: Davis, S.T.]]
+[[Category: Davis, S T.]]
-[[Category: Green, S.M.]]
+[[Category: Green, S M.]]
-[[Category: Johanson, K.O.]]
+[[Category: Johanson, K O.]]
-[[Category: McDevitt, P.J.]]
+[[Category: McDevitt, P J.]]
 [[Category: Zhao, B.]]
 [[Category: Zhao, H.]]
-[[Category: Zhou, B.B.]]
+[[Category: Zhou, B B.]]
 [[Category: SO4]]
 [[Category: STU]]
 [[Category: chk1-staurosporine complex]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 18:26:15 2007''
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