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Human Serine/Threonine Kinase 17B (STK17B) in complex with the kinase compound Quercetin

PDB Code 3LM5 Target Class Protein Kinase Target STK17B + Quercetin Alias DRAK2, STK17B Disease Area/Function signalling Date Deposited Jan 29 2010 Authors Ugochukwu, E., Soundararajan, M., Rellos, P., Fedorov, O., Phillips, C., Wang, J., Hapka, E., Filippakopoulos, P., Chaikuad, A., Pike, A.C.W., Carpenter, L., Vollmar, M., von Delft, F., Bountra, C., Arrowsmith, C. H., Weigelt, J., Edwards, A., Knapp, S. Related Structure 3LM0

About this structure

STK17B, better known as DRAK2, belongs to the family of death-associated protein kinases. It is ubiquitously expressed with highest expression levels detected in organs of the immune system. DRAK2 is predominantly found in the nucleus but phosphorylation at Ser350 located in the nuclear localization signal induces relocalisation form the nucleus to the cytoplasm (Kuwahara et al., 2008). Little is known so far about DRAK2 substrates and regulation of this kinase. The calcineurin B homologous protein 1CHP1 has been reported to inhibit DRAK2 kinase activity, an effect that is Ca2+-dependent (Nagita et al., 2003). Autophosphorylation at Ser12 is induced by antigen receptor stimulation in T and B cells (Friedrich et al., 2007).

DRAK2 is an inducer of apoptosis and thereby regulates T cell survival, activation and development. Knockout mice for DRAK2 confirm this role and show abnormal T cell numbers and increased T cell proliferation as well as abnormal cytokine physiology (McGargill et al., 2004). These mice have also reduced numbers of germinal centers (GC) due to increase of apoptotic GC B and T cells (Al-Qahtani et al., 2008). Surprisingly, Drak2 knockout mice show reduced susceptibility to some but not all models of automimmune diseases like experimental autoimmune encephalomyelitis (EAE) and automimmune diabetes (Ramos et al., 2008), (McGargill et al., 2008). However, loss of Drak2 does not alter the response to an acute viral infection (McGargill et al., 2008). The resistance to certain autoimmune diseases seems to be due to an increased sensitivity of T cell intrinsic. Accordingly, transgenic mice overexpressing DRAK2 ubiquitously develop augmented apoptosis after TCR stimulation with compromised memory T cell development. Pancreatic islet cells of these animals undergo increased apoptosis upon stimulation with inflammatory cytokines resulting in decreased insulin secretion and glucose intolerance when fed a high-fat diet confirming a role for DRAK2 in the development of diabetes (Gatzka et al., 2009), (Mao et al., 2006). DRAK2 also plays a role in tumorigenesis and the effect of cyclooxygenase-2 (COX-2), which is over-expressed in colorectal cancer to render tumour cells resistant to apoptosis is mediated by negatively regulating DRAK2 (Doherty et al., 2009). Here we report the structure of the kinase domain of STK17B in complex with quercetin at 2.3 Å resolution and with the non-specific inhibitor ASC68 at 2.8 Å respectively.

Co-crystallized ligands Figure 1: Co-crystallized ligands.

We would like to thank the group of Prof. Kevan Shokat (University of California San Francisco) for providing the inhibitor ASC68 for co-crystallization studies.

References

  1. Al-Qahtani, A., Xu, Z., Zan, H., Walsh, C.M., and Casali, P. (2008). A role for DRAK2 in the germinal center reaction and the antibody response. Autoimmunity 41, 341-352.
  2. Doherty, G.A., Byrne, S.M., Austin, S.C., Scully, G.M., Sadlier, D.M., Neilan, T.G., Kay, E.W., Murray, F.E., and Fitzgerald, D.J. (2009). Regulation of the apoptosis-inducing kinase DRAK2 by cyclooxygenase-2 in colorectal cancer. Br J Cancer 101, 483-491.
  3. Friedrich, M.L., Cui, M., Hernandez, J.B., Weist, B.M., Andersen, H.M., Zhang, X., Huang, L., and Walsh, C.M. (2007). Modulation of DRAK2 autophosphorylation by antigen receptor signaling in primary lymphocytes. J Biol Chem 282, 4573-4584.
  4. Gatzka, M., Newton, R.H., and Walsh, C.M. (2009). Altered thymic selection and increased autoimmunity caused by ectopic expression of DRAK2 during T cell development. J Immunol 183, 285-297.
  5. Kuwahara, H., Nishizaki, M., and Kanazawa, H. (2008). Nuclear localization signal and phosphorylation of Serine350 specify intracellular localization of DRAK2. J Biochem 143, 349-358.
  6. Mao, J., Qiao, X., Luo, H., and Wu, J. (2006). Transgenic drak2 overexpression in mice leads to increased T cell apoptosis and compromised memory T cell development. J Biol Chem 281, 12587-12595.
  7. McGargill, M.A., Choy, C., Wen, B.G., and Hedrick, S.M. (2008). Drak2 regulates the survival of activated T cells and is required for organ-specific autoimmune disease. J Immunol 181, 7593-7605.
  8. McGargill, M.A., Wen, B.G., Walsh, C.M., and Hedrick, S.M. (2004). A deficiency in Drak2 results in a T cell hypersensitivity and an unexpected resistance to autoimmunity. Immunity 21, 781-791.
  9. Nagita, M., Inoue, H., Nakamura, N., and Kanazawa, H. (2003). Two nuclear export signals specify the cytoplasmic localization of calcineurin B homologous protein 1. J Biochem 134, 919-925.
  10. Ramos, S.J., Hernandez, J.B., Gatzka, M., and Walsh, C.M. (2008). Enhanced T cell apoptosis within Drak2-deficient mice promotes resistance to autoimmunity. J Immunol 181, 7606-7616.