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

Nat Struct Biol. 2001 Oct;8(10):899-907. doi: 10.1038/nsb1001-899.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Amino Acid Sequence
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins
  • Binding Sites
  • Calcium-Calmodulin-Dependent Protein Kinases / chemistry
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Calcium-Calmodulin-Dependent Protein Kinases / physiology
  • Catalytic Domain
  • Crystallography, X-Ray
  • Death-Associated Protein Kinases
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Neoplasms / prevention & control*
  • Protein Conformation
  • Protein Serine-Threonine Kinases / chemistry
  • Protein Serine-Threonine Kinases / metabolism
  • Sequence Homology, Amino Acid
  • Solvents
  • Structure-Activity Relationship

Substances

  • Apoptosis Regulatory Proteins
  • Solvents
  • Adenosine Triphosphate
  • Death-Associated Protein Kinases
  • Protein Serine-Threonine Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases

Associated data

  • PDB/1IG1
  • PDB/1JKK
  • PDB/1JKL
  • PDB/1JKS
  • PDB/1JKT