Crystal structures of the catalytic domain of human protein kinase associated with apoptosis and tumor suppression

We have determined X-ray crystal structures with up to 1.5 Angstrom resolut ion of the catalytic domain of death-associated protein kinase (DAPK), the first described member of a novel family of pro-apoptotic and tumor-suppres sive serine/threonine kinases. The geometry of the active site was studied in the apo form, in a complex with nonhydrolyzable AMPPnP and in a ternary complex consisting of kinase, AMPPnP and either Mg2+ or Mn2+. The structure s revealed a previously undescribed water-mediated stabilization of the int eraction between the lysine that is conserved in protein kinases and the be ta- and gamma -phosphates of ATP, as well as conformational changes at the active site upon ion binding. Comparison between these structures and nucle otide triphosphate complexes of several other kinases disclosed a number of unique features of the DAPK catalytic domain, among which is a highly orde red basic loop in the N-terminal domain that may participate in enzyme regu lation.