The Crystal Structure of Cancer Osaka Thyroid Kinase Reveals an Unexpected Kinase Domain Fold.
2015
Abstract Macrophages are important cellular effectors in innate immune responses and play a major role in autoimmune diseases such as rheumatoid arthritis. Cancer Osaka thyroid (COT)
kinase, also known as
mitogen-activated protein kinase kinasekinase 8 (
MAP3K8) and tumor progression locus 2 (Tpl-2), is a serine-threonine (ST)
kinaseand is a key regulator in the production of pro-inflammatory cytokines in macrophages. Due to its pivotal role in immune biology, COT
kinasehas 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 and cancer. The production of monomeric, recombinant COT
kinasehas 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
kinasethat 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
kinaseinhibitors and to determine the x-ray co-crystal structures of the COT
kinasedomain in complex with two ATP-binding site inhibitors. The structures presented in this study reveal two distinct ligand binding modes and a unique
kinasedomain architecture that has not been observed previously. The structurally versatile active site significantly impacts the design of potent, low molecular weight COT
kinaseinhibitors.
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