4Y85

Crystal structure of COT kinase domain in complex with 5-(5-(1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-1,3,4-oxadiazol-2-amine

4Y85 の概要

• エントリーDOI: 10.2210/pdb4y85/pdb
• 関連するPDBエントリー: 4Y83
• 分子名称: Mitogen-activated protein kinase kinase kinase 8, 5-[5-(1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1,3,4-oxadiazol-2-amine (3 entities in total)
• 機能のキーワード: cot, tpl-2, map3k8, kinase, inhibitor, complex, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 113854.55

構造登録者

Gutmann, S.,Hinniger, A. (登録日: 2015-02-16, 公開日: 2015-05-06, 最終更新日: 2024-05-08)

主引用文献

Gutmann, S.,Hinniger, A.,Fendrich, G.,Druckes, P.,Antz, S.,Mattes, H.,Mobitz, H.,Ofner, S.,Schmiedeberg, N.,Stojanovic, A.,Rieffel, S.,Strauss, A.,Troxler, T.,Glatthar, R.,Sparrer, H.
The Crystal Structure of Cancer Osaka Thyroid Kinase Reveals an Unexpected Kinase Domain Fold.
J.Biol.Chem., 290:15210-15218, 2015

PubMed 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 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 pro-inflammatory 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 and cancer. 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 study reveal two distinct ligand binding modes and a unique kinase domain architecture that has not been observed previously. The structurally versatile active site significantly impacts the design of potent, low molecular weight COT kinase inhibitors.

PubMed: 25918157
DOI: 10.1074/jbc.M115.648097

実験手法

X-RAY DIFFRACTION (2.33 Å)