1eh4
From Proteopedia
(New page: 200px<br /><applet load="1eh4" size="450" color="white" frame="true" align="right" spinBox="true" caption="1eh4, resolution 2.80Å" /> '''BINARY COMPLEX OF CA...) |
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| - | [[Image:1eh4.jpg|left|200px]]<br /><applet load="1eh4" size=" | + | [[Image:1eh4.jpg|left|200px]]<br /><applet load="1eh4" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1eh4, resolution 2.80Å" /> | caption="1eh4, resolution 2.80Å" /> | ||
'''BINARY COMPLEX OF CASEIN KINASE-1 FROM S. POMBE WITH AN ATP COMPETITIVE INHIBITOR, IC261'''<br /> | '''BINARY COMPLEX OF CASEIN KINASE-1 FROM S. POMBE WITH AN ATP COMPETITIVE INHIBITOR, IC261'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Members of the casein kinase-1 family of protein kinases play an essential | + | Members of the casein kinase-1 family of protein kinases play an essential role in cell regulation and disease pathogenesis. Unlike most protein kinases, they appear to function as constitutively active enzymes. As a result, selective pharmacological inhibitors can play an important role in dissection of casein kinase-1-dependent processes. To address this need, new small molecule inhibitors of casein kinase-1 acting through ATP-competitive and ATP-noncompetitive mechanisms were isolated on the basis of in vitro screening. Here we report the crystal structure of 3-[(2,4,6-trimethoxyphenyl) methylidenyl]-indolin-2-one (IC261), an ATP-competitive inhibitor with differential activity among casein kinase-1 isoforms, in complex with the catalytic domain of fission yeast casein kinase-1 refined to a crystallographic R-factor of 22.4% at 2.8 A resolution. The structure reveals that IC261 stabilizes casein kinase-1 in a conformation midway between nucleotide substrate liganded and nonliganded conformations. We propose that adoption of this conformation by casein kinase-1 family members stabilizes a delocalized network of side chain interactions and results in a decreased dissociation rate of inhibitor. |
==About this Structure== | ==About this Structure== | ||
| - | 1EH4 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 IC1 as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | + | 1EH4 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=IC1:'>IC1</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EH4 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Schizosaccharomyces pombe]] | [[Category: Schizosaccharomyces pombe]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Bergmeier, S | + | [[Category: Bergmeier, S C.]] |
| - | [[Category: Demaggio, A | + | [[Category: Demaggio, A J.]] |
[[Category: Egli, M.]] | [[Category: Egli, M.]] | ||
| - | [[Category: Hoekstra, M | + | [[Category: Hoekstra, M F.]] |
[[Category: Kuret, J.]] | [[Category: Kuret, J.]] | ||
[[Category: Mashhoon, N.]] | [[Category: Mashhoon, N.]] | ||
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[[Category: protein-inhibitor binary complex]] | [[Category: protein-inhibitor binary complex]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:27:40 2008'' |
Revision as of 10:27, 21 February 2008
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BINARY COMPLEX OF CASEIN KINASE-1 FROM S. POMBE WITH AN ATP COMPETITIVE INHIBITOR, IC261
Overview
Members of the casein kinase-1 family of protein kinases play an essential role in cell regulation and disease pathogenesis. Unlike most protein kinases, they appear to function as constitutively active enzymes. As a result, selective pharmacological inhibitors can play an important role in dissection of casein kinase-1-dependent processes. To address this need, new small molecule inhibitors of casein kinase-1 acting through ATP-competitive and ATP-noncompetitive mechanisms were isolated on the basis of in vitro screening. Here we report the crystal structure of 3-[(2,4,6-trimethoxyphenyl) methylidenyl]-indolin-2-one (IC261), an ATP-competitive inhibitor with differential activity among casein kinase-1 isoforms, in complex with the catalytic domain of fission yeast casein kinase-1 refined to a crystallographic R-factor of 22.4% at 2.8 A resolution. The structure reveals that IC261 stabilizes casein kinase-1 in a conformation midway between nucleotide substrate liganded and nonliganded conformations. We propose that adoption of this conformation by casein kinase-1 family members stabilizes a delocalized network of side chain interactions and results in a decreased dissociation rate of inhibitor.
About this Structure
1EH4 is a Single protein structure of sequence from Schizosaccharomyces pombe with and as ligands. Full crystallographic information is available from OCA.
Reference
Crystal structure of a conformation-selective casein kinase-1 inhibitor., Mashhoon N, DeMaggio AJ, Tereshko V, Bergmeier SC, Egli M, Hoekstra MF, Kuret J, J Biol Chem. 2000 Jun 30;275(26):20052-60. PMID:10749871
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