1eh4
From Proteopedia
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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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