Structural basis for the interaction between casein kinase 1 delta and a potent and selective inhibitor

J Med Chem. 2012 Jan 26;55(2):956-60. doi: 10.1021/jm201387s. Epub 2012 Jan 5.

Abstract

Casein kinase 1 delta (CK1δ) and its closest homologue CK1ε are key regulators of diverse cellular growth and survival processes such as Wnt signaling, DNA repair, and circadian rhythms. We report three crystal structures of the kinase domain of human CK1δ, one apo and two complexed with a potent and selective CK1δ/ε inhibitor PF670462 in two different crystal forms. These structures provide a molecular basis for the strong and specific inhibitor interactions and suggest clues for further development of CK1δ/ε inhibitors.

MeSH terms

  • Amino Acid Sequence
  • Apoenzymes / antagonists & inhibitors
  • Apoenzymes / chemistry
  • Casein Kinase 1 epsilon / antagonists & inhibitors
  • Casein Kinase 1 epsilon / chemistry
  • Casein Kinase Idelta / antagonists & inhibitors*
  • Casein Kinase Idelta / chemistry
  • Catalytic Domain
  • Crystallography, X-Ray
  • Humans
  • Imidazoles / chemistry*
  • Ligands
  • Models, Molecular*
  • Molecular Sequence Data
  • Protein Conformation
  • Pyrimidines / chemistry*
  • Quantitative Structure-Activity Relationship

Substances

  • Apoenzymes
  • Imidazoles
  • Ligands
  • Pyrimidines
  • PF-670462
  • Casein Kinase 1 epsilon
  • Casein Kinase Idelta

Associated data

  • PDB/3UYS
  • PDB/3UYT
  • PDB/3UZP