5V5N

Crystal structure of Takinib bound to TAK1

5V5N の概要

• エントリーDOI: 10.2210/pdb5v5n/pdb
• 分子名称: Mitogen-activated protein kinase kinase kinase 7/TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 chimera, N~1~-(1-propyl-1,3-dihydro-2H-benzimidazol-2-ylidene)benzene-1,3-dicarboxamide (3 entities in total)
• 機能のキーワード: tak1, inhibitor, hydrogen bond, dfg-in, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35103.47

構造登録者

Gurbani, D.,Westover, K.,Bera, A.K. (登録日: 2017-03-14, 公開日: 2017-08-30, 最終更新日: 2023-10-04)

主引用文献

Totzke, J.,Gurbani, D.,Raphemot, R.,Hughes, P.F.,Bodoor, K.,Carlson, D.A.,Loiselle, D.R.,Bera, A.K.,Eibschutz, L.S.,Perkins, M.M.,Eubanks, A.L.,Campbell, P.L.,Fox, D.A.,Westover, K.D.,Haystead, T.A.J.,Derbyshire, E.R.
Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-alpha Inhibition for Cancer and Autoimmune Disease.
Cell Chem Biol, 24:1029-1039.e7, 2017

PubMed Abstract: Tumor necrosis factor alpha (TNF-α) has both positive and negative roles in human disease. In certain cancers, TNF-α is infused locally to promote tumor regression, but dose-limiting inflammatory effects limit broader utility. In autoimmune disease, anti-TNF-α antibodies control inflammation in most patients, but these benefits are offset during chronic treatment. TAK1 acts as a key mediator between survival and cell death in TNF-α-mediated signaling. Here, we describe Takinib, a potent and selective TAK1 inhibitor that induces apoptosis following TNF-α stimulation in cell models of rheumatoid arthritis and metastatic breast cancer. We demonstrate that Takinib is an inhibitor of autophosphorylated and non-phosphorylated TAK1 that binds within the ATP-binding pocket and inhibits by slowing down the rate-limiting step of TAK1 activation. Overall, Takinib is an attractive starting point for the development of inhibitors that sensitize cells to TNF-α-induced cell death, with general implications for cancer and autoimmune disease treatment.

PubMed: 28820959
DOI: 10.1016/j.chembiol.2017.07.011

実験手法

X-RAY DIFFRACTION (2.006 Å)