Crystal Structures of Interleukin-2 Tyrosine Kinase and Their Implications for the Design of Selective Inhibitors

• Published in: The Journal of biological chemistry Vol. 279; no. 18; pp. 18727 - 18732
• Main Authors: Brown, Kieron, Long, Joanna M, Vial, Sarah C M, Dedi, Neesha, Dunster, Nicholas J, Renwick, Suzanne B, Tanner, Adam J, Frantz, J Dan, Fleming, Mark A, Cheetham, Graham M T
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 30.04.2004
• Subjects: Adenosine Triphosphate - chemistry; Animals; Binding Sites; Crystallography, X-Ray; Drug Design; Enzyme Inhibitors - chemistry; Humans; Molecular Structure; Phosphorylation; Protein Binding; Protein Conformation; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - chemistry; Staurosporine - chemistry
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M400031200

Interleukin-2 tyrosine kinase, Itk, is an important member of the Tec family of non-receptor tyrosine kinases that play a central role in signaling through antigen receptors such as the T-cell receptor, B-cell receptor, and Fcϵ. Selective inhibition of Itk may be an important way of modulating many diseases involving heightened or inappropriate activation of the immune system. In addition to an unliganded nonphophorylated Itk catalytic kinase domain, we determined the crystal structures of the phosphorylated and nonphosphorylated kinase domain bound to staurosporine, a potent broad-spectrum kinase inhibitor. These structures are useful for the design of novel, highly potent and selective Itk inhibitors and provide insight into the influence of inhibitor binding and phosphorylation on the conformation of Itk.