| Structural highlights
4m12 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: |
| | Related: | 4m0y, 4m0z, 4m13, 4m14, 4m15 |
| Gene: | ITK, EMT, LYK (HUMAN) |
| Activity: | Non-specific protein-tyrosine kinase, with EC number 2.7.10.2 |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Disease
[ITK_HUMAN] Defects in ITK are the cause of lymphoproliferative syndrome EBV-associated autosomal type 1 (LPSA1) [MIM:613011]. LPSA1 is a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Inadequate immune response to EBV can have a fatal outcome. Clinical features include splenomegaly, lymphadenopathy, anemia, thrombocytopenia, pancytopenia, recurrent infections. There is an increased risk for lymphoma.[1]
Function
[ITK_HUMAN] Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation and full activation. Once activated, phosphorylates PLCG1, leading to the activation of this lipase and subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation.[2] [3] [4]
Publication Abstract from PubMed
IL-2-induced T cell kinase (ITK) is a critical component of signal transduction in T cells and has a well-validated role in their proliferation, cytokine release and chemotaxis. ITK is an attractive target for the treatment of T-cell mediated inflammatory diseases. Here we describe the discovery of kinase inhibitors that preferentially bind to an allosteric pocket of ITK. The novel ITK allosteric site was characterized by NMR, surface plasmon resonance, isothermal titration calorimetry, enzymology, and X-ray crystallography. Initial screening hits bound to both the allosteric pocket and the ATP site. Successful lead optimization was achieved by improving the contribution of the allosteric component to the overall inhibition. NMR competition experiments demonstrated that the dual-site binders showed higher affinity for the allosteric site compared to the ATP site. Moreover, an optimized inhibitor displayed non-competitive inhibition with respect to ATP as shown by steady-state enzyme kinetics. The activity of the isolated kinase domain and auto-activation of the full-length enzyme were inhibited with similar potency. However, inhibition of the activated full-length enzyme was weaker, presumably because the allosteric site is altered when ITK becomes activated. An optimized lead showed exquisite kinome selectivity and is efficacious in human whole blood and proximal cell-based assays.
Selectively targeting an inactive conformation of IL-2-induced T cell kinase by allosteric inhibitors.,Han S, Czerwinski RM, Caspers NL, Limburg DC, Ding W, Wang H, Ohren JF, Rajamohan F, McLellan TJ, Unwalla R, Choi C, Parikh MD, Seth N, Edmonds J, Phillips C, Shakya S, Li X, Spaulding V, Hughes S, Cook A, Robinson C, Mathias JP, Navratilova I, Medley QG, Anderson DR, Kurumbail RG, Aulabaugh A Biochem J. 2014 Mar 4. PMID:24593284[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Huck K, Feyen O, Niehues T, Ruschendorf F, Hubner N, Laws HJ, Telieps T, Knapp S, Wacker HH, Meindl A, Jumaa H, Borkhardt A. Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation. J Clin Invest. 2009 May;119(5):1350-8. PMID:19425169
- ↑ Perez-Villar JJ, Whitney GS, Sitnick MT, Dunn RJ, Venkatesan S, O'Day K, Schieven GL, Lin TA, Kanner SB. Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav. Biochemistry. 2002 Aug 27;41(34):10732-40. PMID:12186560
- ↑ Grasis JA, Browne CD, Tsoukas CD. Inducible T cell tyrosine kinase regulates actin-dependent cytoskeletal events induced by the T cell antigen receptor. J Immunol. 2003 Apr 15;170(8):3971-6. PMID:12682224
- ↑ Sela M, Bogin Y, Beach D, Oellerich T, Lehne J, Smith-Garvin JE, Okumura M, Starosvetsky E, Kosoff R, Libman E, Koretzky G, Kambayashi T, Urlaub H, Wienands J, Chernoff J, Yablonski D. Sequential phosphorylation of SLP-76 at tyrosine 173 is required for activation of T and mast cells. EMBO J. 2011 Jul 1;30(15):3160-72. doi: 10.1038/emboj.2011.213. PMID:21725281 doi:10.1038/emboj.2011.213
- ↑ Han S, Czerwinski RM, Caspers NL, Limburg DC, Ding W, Wang H, Ohren JF, Rajamohan F, McLellan TJ, Unwalla R, Choi C, Parikh MD, Seth N, Edmonds J, Phillips C, Shakya S, Li X, Spaulding V, Hughes S, Cook A, Robinson C, Mathias JP, Navratilova I, Medley QG, Anderson DR, Kurumbail RG, Aulabaugh A. Selectively targeting an inactive conformation of IL-2-induced T cell kinase by allosteric inhibitors. Biochem J. 2014 Mar 4. PMID:24593284 doi:http://dx.doi.org/10.1042/BJ20131139
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