title: Crystal structure of a conformation-selective casein kinase-1 inhibitor.
abstract: 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.
authors.affiliation: Center for Biotechnology, Ohio State University College of Medicine, Columbus, Ohio 43210, ICOS Corporation, Bothell, Washington 98021, USA.
authors.forename: N
authors.initials: N
authors.lastname: Mashhoon
authors.forename: A J
authors.initials: AJ
authors.lastname: DeMaggio
authors.forename: V
authors.initials: V
authors.lastname: Tereshko
authors.forename: S C
authors.initials: SC
authors.lastname: Bergmeier
authors.forename: M
authors.initials: M
authors.lastname: Egli
authors.forename: M F
authors.initials: MF
authors.lastname: Hoekstra
authors.forename: J
authors.initials: J
authors.lastname: Kuret
mesh_terms: D047388:Casein Kinases; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D000078183:Oxindoles; D019151:Peptide Library; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D010770:Phosphotransferases / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects; D020033:Protein Isoforms / Q000737:chemistry; D047428:Protein Kinase Inhibitors; D017434:Protein Structure, Tertiary; D012568:Schizosaccharomyces / Q000201:enzymology; D055672:Static Electricity
chemical_list: D004791:Enzyme Inhibitors; C411652:IC 261; D007211:Indoles; D000078183:Oxindoles; D019151:Peptide Library; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; C022960:2-oxindole; D010696:Phloroglucinol; D010770:Phosphotransferases; D047388:Casein Kinases