1EH4: Binary Complex Of Casein Kinase-1 From S. Pombe With An Atp Competitive Inhibitor, Ic261

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.
PDB ID: 1EH4Download
MMDB ID: 17326
PDB Deposition Date: 2000/2/18
Updated in MMDB: 2017/10
Experimental Method:
x-ray diffraction
Resolution: 2.8  Å
Source Organism:
Similar Structures:
Biological Unit for 1EH4: monomeric; determined by author
Molecular Components in 1EH4
Label Count Molecule
Protein (1 molecule)
Casein Kinase-1(Gene symbol: cki1)
Molecule annotation
Chemicals (8 molecules)
* Click molecule labels to explore molecular sequence information.

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