5CWZ
Crystal structure of the kinase domain of human TRAF2 and NCK-interacting protein kinase
Summary for 5CWZ
| Entry DOI | 10.2210/pdb5cwz/pdb |
| Descriptor | TRAF2 and NCK-interacting protein kinase (2 entities in total) |
| Functional Keywords | kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 3 |
| Total formula weight | 105228.98 |
| Authors | Ohbayashi, N.,Kukimoto-Niino, M.,Yamada, T.,Shirouzu, M. (deposition date: 2015-07-28, release date: 2016-07-27, Last modification date: 2023-11-08) |
| Primary citation | Masuda, M.,Uno, Y.,Ohbayashi, N.,Ohata, H.,Mimata, A.,Kukimoto-Niino, M.,Moriyama, H.,Kashimoto, S.,Inoue, T.,Goto, N.,Okamoto, K.,Shirouzu, M.,Sawa, M.,Yamada, T. TNIK inhibition abrogates colorectal cancer stemness Nat Commun, 7:12586-12586, 2016 Cited by PubMed Abstract: Canonical Wnt/β-catenin signalling is essential for maintaining intestinal stem cells, and its constitutive activation has been implicated in colorectal carcinogenesis. We and others have previously identified Traf2- and Nck-interacting kinase (TNIK) as an essential regulatory component of the T-cell factor-4 and β-catenin transcriptional complex. Consistent with this, Tnik-deficient mice are resistant to azoxymethane-induced colon tumorigenesis, and Tnik(-/-)/Apc(min/+) mutant mice develop significantly fewer intestinal tumours. Here we report the first orally available small-molecule TNIK inhibitor, NCB-0846, having anti-Wnt activity. X-ray co-crystal structure analysis reveals that NCB-0846 binds to TNIK in an inactive conformation, and this binding mode seems to be essential for Wnt inhibition. NCB-0846 suppresses Wnt-driven intestinal tumorigenesis in Apc(min/+) mice and the sphere- and tumour-forming activities of colorectal cancer cells. TNIK is required for the tumour-initiating function of colorectal cancer stem cells. Its inhibition is a promising therapeutic approach. PubMed: 27562646DOI: 10.1038/ncomms12586 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.9 Å) |
Structure validation
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