4ZY3

Crystal Structure of Keap1 in Complex with a small chemical compound, K67

Summary for 4ZY3

• Entry DOI: 10.2210/pdb4zy3/pdb
• Descriptor: Kelch-like ECH-associated protein 1, FORMIC ACID, N,N'-[2-(2-oxopropyl)naphthalene-1,4-diyl]bis(4-ethoxybenzenesulfonamide), ... (4 entities in total)
• Functional Keywords: nrf2, keap1, stress sensor, small molecule binding, double glycine repeat, kelch domain, p62, transcription
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 2
• Total formula weight: 69797.64

Authors

Fukutomi, T.,Iso, T.,Suzuki, T.,Takagi, K.,Mizushima, T.,Komatsu, M.,Yamamoto, M. (deposition date: 2015-05-21, release date: 2016-05-25, Last modification date: 2024-10-16)

Primary citation

Saito, T.,Ichimura, Y.,Taguchi, K.,Suzuki, T.,Mizushima, T.,Takagi, K.,Hirose, Y.,Nagahashi, M.,Iso, T.,Fukutomi, T.,Ohishi, M.,Endo, K.,Uemura, T.,Nishito, Y.,Okuda, S.,Obata, M.,Kouno, T.,Imamura, R.,Tada, Y.,Obata, R.,Yasuda, D.,Takahashi, K.,Fujimura, T.,Pi, J.,Lee, M.S.,Ueno, T.,Ohe, T.,Mashino, T.,Wakai, T.,Kojima, H.,Okabe, T.,Nagano, T.,Motohashi, H.,Waguri, S.,Soga, T.,Yamamoto, M.,Tanaka, K.,Komatsu, M.
p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming
Nat Commun, 7:12030-12030, 2016

PubMed Abstract: p62/Sqstm1 is a multifunctional protein involved in cell survival, growth and death, that is degraded by autophagy. Amplification of the p62/Sqstm1 gene, and aberrant accumulation and phosphorylation of p62/Sqstm1, have been implicated in tumour development. Herein, we reveal the molecular mechanism of p62/Sqstm1-dependent malignant progression, and suggest that molecular targeting of p62/Sqstm1 represents a potential chemotherapeutic approach against hepatocellular carcinoma (HCC). Phosphorylation of p62/Sqstm1 at Ser349 directs glucose to the glucuronate pathway, and glutamine towards glutathione synthesis through activation of the transcription factor Nrf2. These changes provide HCC cells with tolerance to anti-cancer drugs and proliferation potency. Phosphorylated p62/Sqstm1 accumulates in tumour regions positive for hepatitis C virus (HCV). An inhibitor of phosphorylated p62-dependent Nrf2 activation suppresses the proliferation and anticancer agent tolerance of HCC. Our data indicate that this Nrf2 inhibitor could be used to make cancer cells less resistant to anticancer drugs, especially in HCV-positive HCC patients.

PubMed: 27345495
DOI: 10.1038/ncomms12030

Experimental method

X-RAY DIFFRACTION (1.8 Å)