S. pombe CASEIN KINASE-1 (EC.2.7.1-)
Recombinant Catalytic Core (2-298) Complexed with CKI7 (N-(2-Aminoethyl)-5-Chloroisoquinoline-8-Sulfonamide)
A large family of isoquinoline sulfonamide compounds inhibits protein kinases by competing with
adenosine triphosphates(ATP), yet interferes little with the activity of other ATP-using enzymes
such as ATPases and adenylate cyclases. One such compound,
N-(2-aminoethyl)-5-chloroisoquinoline-8-sulfonamide (CK17), is selective for casein kinase-1
isolated from a variety of sources. Here we report the crystal structure of the catalytic domain of
Schizosaccharomyces pombe casein kinase-1 complexed with CK17, refined to a crystallographic
R-factor of 17.8% at 2.5 angstrom resolution. The structure provides new insights into the
mechanism of the ATP-competing inhibition and the origin of their selectivity toward different
protein kinases. Selectivity for protein kinases versus other enzymes is achieved by hydrophobic
contacts and the hydrogen bond with isoquinoline ring. We propose that the hydrogen bond
involving the ring nitrogen-2 atom of the isoquinoline must be preserved, but that the ring can flip
depending on the chemical substituents at ring positions 5 and 8. Selectivity for individual
members of the protein kinase family is achieved primarily by interactions with these substituents.
 Xu RM; Carmel G; Kuret J; Cheng X (1996) Proc Nat Acad Sci USA
 Xu R-M; Carmel G; Sweet RM; Kuret J; Cheng X (1995) Crystal structure of casein kinase-1, a phosphate-directed protein kinase.
EMBO J 14: 1015. [Abstract]
 Carmel G; Leichus B, Cheng X; Patterson SD; Mirza U; Chait BT; Kuret J (1994) Expression, purifictaion, crystalization, and preliminary x-ray analysis of casein kinase-1 from Schizosaccharomyces pombe.
J Biol Chem 269: 7304-7309. [Abstract]
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