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 A resolution of the catalytic domain of death-associated protein kinase (DAPK), the first described member of a novel family of pro-apoptotic and tumor-suppressive 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 structures revealed a previously undescribed water-mediated stabilization of the interaction between the lysine that is conserved in protein kinases and the beta- and gamma-phosphates of ATP, as well as conformational changes at the active site upon ion binding. Comparison between these structures and nucleotide triphosphate complexes of several other kinases disclosed a number of unique features of the DAPK catalytic domain, among which is a highly ordered basic loop in the N-terminal domain that may participate in enzyme regulation.
Tereshko
V
V
Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37235, USA.
Teplova
M
M
Brunzelle
J
J
Watterson
D M
DM
Egli
M
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001665:Binding Sites; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D064550:Death-Associated Protein Kinases; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000517:prevention & control*; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012997:Solvents; D013329:Structure-Activity Relationship
D051017:Apoptosis Regulatory Proteins; D012997:Solvents; D000255:Adenosine Triphosphate; D064550:Death-Associated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases