STRUCTURAL BASIS FOR SELECTIVITY OF THE ISOQUINOLINE SULFONAMIDE FAMILY OF PROTEIN-KINASE INHIBITORS

A large family of isoquinoline sulfonamide compounds inhibits protein kinases by competing with adenosine triphosphates (ATP), yet interfere s little with the activity of other ATP-using enzymes such as ATPases and adenylate cyclases. One such compound, -(2-aminoethyl)-5-chloroiso quinoline-8-sulfonamide (CKI7), is selective for casein kinase-1 isola ted from a variety of sources, Here we report the crystal structure of the catalytic domain of Schizosaccharomyces pombe casein kinase-1 com plexed with CKI7, refined to a crystallographic R-factor of 17.8% at 2 .5 Angstrom resolution, The structure provides new insights into the m echanism of the ATP-competing inhibition and the origin of their selec tivity toward different protein kinases, Selectivity for protein kinas es versus other enzymes is achieved by hydrophobic contacts and the hy drogen bond with isoquinoline ring, We propose that the hydrogen bond involving the ring nitrogen-2 atom of the isoquinoline must be preserv ed, but that the ring can flip depending on the chemical substituents at ring positions 5 and 8, Selectivity for individual members of the p rotein kinase family is achieved primarily by interactions with these substituents.