2csn: Difference between revisions

Revision as of 17:52, 21 February 2008

BINARY COMPLEX OF CASEIN KINASE-1 WITH CKI7

OverviewOverview

A large family of isoquinoline sulfonamide compounds inhibits protein kinases by competing with adenosine triphosphates(ATP), yet interferes little with the activity of other ATP-using enzymes such as ATPases and adenylate cyclases. One such compound, N-(2-aminoethyl)-5-chloroisoquinoline-8-sulfonamide (CK17), is selective for casein kinase-1 isolated from a variety of sources. Here we report the crystal structure of the catalytic domain of Schizosaccharomyces pombe casein kinase-1 complexed with CK17, refined to a crystallographic R-factor of 17.8% at 2.5 angstrom resolution. The structure provides new insights into the mechanism of the ATP-competing inhibition and the origin of their selectivity toward different protein kinases. Selectivity for protein kinases versus other enzymes is achieved by hydrophobic contacts and the hydrogen bond with isoquinoline ring. We propose that the hydrogen bond involving the ring nitrogen-2 atom of the isoquinoline must be preserved, but that the ring can flip depending on the chemical substituents at ring positions 5 and 8. Selectivity for individual members of the protein kinase family is achieved primarily by interactions with these substituents.

About this StructureAbout this Structure

2CSN is a Single protein structure of sequence from Schizosaccharomyces pombe with and as ligands. Full crystallographic information is available from OCA.

ReferenceReference

Structural basis for selectivity of the isoquinoline sulfonamide family of protein kinase inhibitors., Xu RM, Carmel G, Kuret J, Cheng X, Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6308-13. PMID:8692811

Page seeded by OCA on Thu Feb 21 16:51:59 2008

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OCA

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-[[Image:2csn.jpg|left|200px]]<br /><applet load="2csn" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:2csn.jpg|left|200px]]<br /><applet load="2csn" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="2csn, resolution 2.50&Aring;" />
 '''BINARY COMPLEX OF CASEIN KINASE-1 WITH CKI7'''<br />
 ==Overview==
-A large family of isoquinoline sulfonamide compounds inhibits protein, kinases by competing with adenosine triphosphates(ATP), yet interferes, little with the activity of other ATP-using enzymes such as ATPases and, adenylate cyclases. One such compound, N-(2-aminoethyl)-5-chloroisoquinoline-8-sulfonamide (CK17), is selective, for casein kinase-1 isolated from a variety of sources. Here we report the, crystal structure of the catalytic domain of Schizosaccharomyces pombe, casein kinase-1 complexed with CK17, refined to a crystallographic, R-factor of 17.8% at 2.5 angstrom resolution. The structure provides new, insights into the mechanism of the ATP-competing inhibition and the origin, of their selectivity toward different protein kinases. Selectivity for, protein kinases versus other enzymes is achieved by hydrophobic contacts, and the hydrogen bond with isoquinoline ring. We propose that the hydrogen, bond involving the ring nitrogen-2 atom of the isoquinoline must be, preserved, but that the ring can flip depending on the chemical, substituents at ring positions 5 and 8. Selectivity for individual members, of the protein kinase family is achieved primarily by interactions with, these substituents.
+A large family of isoquinoline sulfonamide compounds inhibits protein kinases by competing with adenosine triphosphates(ATP), yet interferes little with the activity of other ATP-using enzymes such as ATPases and adenylate cyclases. One such compound, N-(2-aminoethyl)-5-chloroisoquinoline-8-sulfonamide (CK17), is selective for casein kinase-1 isolated from a variety of sources. Here we report the crystal structure of the catalytic domain of Schizosaccharomyces pombe casein kinase-1 complexed with CK17, refined to a crystallographic R-factor of 17.8% at 2.5 angstrom resolution. The structure provides new insights into the mechanism of the ATP-competing inhibition and the origin of their selectivity toward different protein kinases. Selectivity for protein kinases versus other enzymes is achieved by hydrophobic contacts and the hydrogen bond with isoquinoline ring. We propose that the hydrogen bond involving the ring nitrogen-2 atom of the isoquinoline must be preserved, but that the ring can flip depending on the chemical substituents at ring positions 5 and 8. Selectivity for individual members of the protein kinase family is achieved primarily by interactions with these substituents.
 ==About this Structure==
-CSN is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Schizosaccharomyces_pombe Schizosaccharomyces pombe] with SO4 and CKI as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2CSN OCA].
+CSN is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Schizosaccharomyces_pombe Schizosaccharomyces pombe] with <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=CKI:'>CKI</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2CSN OCA].
 ==Reference==
@@ Line 14: / Line 14: @@
 [[Category: Single protein]]
 [[Category: Cheng, X.]]
-[[Category: Xu, R.M.]]
+[[Category: Xu, R M.]]
 [[Category: CKI]]
 [[Category: SO4]]
 [[Category: casein kinase-1]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 09:14:43 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:51:59 2008''