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 275 (26): 20052-60

PMID: 10749871 · DOI:10.1074/jbc.M001713200

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.

MeSH Terms (23)

Casein Kinases Computer Simulation Crystallography, X-Ray Enzyme Inhibitors Humans Hydrogen Bonding Indoles Inhibitory Concentration 50 Kinetics Models, Molecular Molecular Sequence Data Mutation Oxindoles Peptide Library Phloroglucinol Phosphotransferases Protein Binding Protein Conformation Protein Isoforms Protein Kinase Inhibitors Protein Structure, Tertiary Schizosaccharomyces Static Electricity

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