Structural basis for the inhibition of tyrosine kinase activity of ZAP-70

Cell. 2007 May 18;129(4):735-46. doi: 10.1016/j.cell.2007.03.039.


ZAP-70, a cytoplasmic tyrosine kinase required for T cell antigen receptor signaling, is controlled by a regulatory segment that includes a tandem SH2 unit responsible for binding to immunoreceptor tyrosine-based activation motifs (ITAMs). The crystal structure of autoinhibited ZAP-70 reveals that the inactive kinase domain adopts a conformation similar to that of cyclin-dependent kinases and Src kinases. The autoinhibitory mechanism of ZAP-70 is, however, distinct and involves interactions between the regulatory segment and the hinge region of the kinase domain that reduce its flexibility. Two tyrosine residues in the SH2-kinase linker that activate ZAP-70 when phosphorylated are involved in aromatic-aromatic interactions that connect the linker to the kinase domain. These interactions are inconsistent with ITAM binding, suggesting that destabilization of this autoinhibited ZAP-70 conformation is the first step in kinase activation.

MeSH terms

  • Amino Acid Motifs / physiology
  • Animals
  • Antigen Presentation / physiology*
  • Binding Sites / physiology
  • Cell Line
  • Crystallography, X-Ray
  • Enzyme Activation / physiology
  • Enzyme Repression / physiology
  • Humans
  • Models, Molecular
  • Phosphorylation
  • Protein Binding / physiology
  • Protein Conformation
  • T-Lymphocytes / enzymology*
  • ZAP-70 Protein-Tyrosine Kinase / chemistry*
  • ZAP-70 Protein-Tyrosine Kinase / metabolism*
  • src Homology Domains / physiology


  • ZAP-70 Protein-Tyrosine Kinase