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The Crystal structure of the cancer osaka thyroid kinase reveals an unexpected kinase domain fold

Gutmann, Sascha, Hinniger, Alexandra, Fendrich, Gabriele, Drueckes, Peter, Antz, Sylvie, Mattes, Henri, Moebitz, Henrik, Ofner, Silvio, Schmiedeberg, Niko, Stojanovic, Aleksandar, Rieffel, Sebastien, Strauss, Andre, Troxler, Thomas J., Sparrer, Helmut and Glatthar, Ralf (2015) The Crystal structure of the cancer osaka thyroid kinase reveals an unexpected kinase domain fold. The Journal of Biological Chemistry, 290 (24). ISSN 0021-92581083-351X


Macrophages are important cellular effectors in innate immune responses and play a major role in autoimmune disorders such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Cancer Osaka Thyroid (COT) kinase, also known as mitogen-activated protein kinase kinase kinase 8 (MAP3K8) and tumor progression locus 2 (Tpl-2), is a Serine-Threonine (ST) kinase and is a key regulator in the production of proinflammatory cytokines in macrophages. Due to its pivotal role in immune biology, COT kinase has been identified as an attractive target for pharmaceutical research that is directed at the discovery of orally available, selective and potent inhibitors for the treatment of autoimmune disorders. The production of monomeric, recombinant COT kinase has proven to be very difficult and issues with solubility and stability of the enzyme have hampered the discovery and optimization of potent and selective inhibitors. We developed a protocol for the production of recombinant human COT kinase that yields pure and highly active enzyme in sufficient yields for biochemical and structural studies. The quality of the enzyme allowed us to establish a robust in vitro phosphorylation assay for the efficient biochemical characterization of COT kinase inhibitors and to determine the X-ray co-crystal structures of the COT kinase domain in complex with two ATP-binding site inhibitors. The structures presented in this publication reveal two distinct ligand binding modes and a unique kinase domain architecture that has not been observed previously. The glycine-rich loop contains a 15 amino acid insert that forms a β-hairpin structure and partially covers the ATP-binding site cleft, which – together with the structurally versatile active site – significantly impacts the design of potent, low-molecular weight COT inhibitors.

Item Type: Article
Keywords: COT kinase, crystal structure, drug discovery, biological sciences, autoimmunity, inflammation, macrophages
Date Deposited: 13 Oct 2015 13:11
Last Modified: 04 Jul 2016 23:45


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