5HZX

Crystal structure of zebrafish MTH1 in complex with TH588

Summary for 5HZX

• Entry DOI: 10.2210/pdb5hzx/pdb
• Related: 4N1U
• Descriptor: Nudix (Nucleoside diphosphate linked moiety X)-type motif 1, N~4~-cyclopropyl-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine, SULFATE ION, ... (7 entities in total)
• Functional Keywords: inhibitor, complex, mth1, th588, hydrolase
• Biological source: Danio rerio (Zebrafish)
• Total number of polymer chains: 2
• Total formula weight: 41760.10

Authors

Narwal, M.,Gustafsson, R.,Brautigam, L.,Pudelko, L.,Jemth, A.-S.,Gad, H.,Karsten, S.,Carreras-Puigvert, J.,Homan, E.,Berndt, C.,Berglund, U.W.,Helleday, T.,Stenmark, P. (deposition date: 2016-02-03, release date: 2016-02-10, Last modification date: 2024-01-10)

Primary citation

Brautigam, L.,Pudelko, L.,Jemth, A.S.,Gad, H.,Narwal, M.,Gustafsson, R.,Karsten, S.,Carreras Puigvert, J.,Homan, E.,Berndt, C.,Berglund, U.W.,Stenmark, P.,Helleday, T.
Hypoxic Signaling and the Cellular Redox Tumor Environment Determine Sensitivity to MTH1 Inhibition.
Cancer Res., 76:2366-2375, 2016

PubMed Abstract: Cancer cells are commonly in a state of redox imbalance that drives their growth and survival. To compensate for oxidative stress induced by the tumor redox environment, cancer cells upregulate specific nononcogenic addiction enzymes, such as MTH1 (NUDT1), which detoxifies oxidized nucleotides. Here, we show that increasing oxidative stress in nonmalignant cells induced their sensitization to the effects of MTH1 inhibition, whereas decreasing oxidative pressure in cancer cells protected against inhibition. Furthermore, we purified zebrafish MTH1 and solved the crystal structure of MTH1 bound to its inhibitor, highlighting the zebrafish as a relevant tool to study MTH1 biology. Delivery of 8-oxo-dGTP and 2-OH-dATP to zebrafish embryos was highly toxic in the absence of MTH1 activity. Moreover, chemically or genetically mimicking activated hypoxia signaling in zebrafish revealed that pathologic upregulation of the HIF1α response, often observed in cancer and linked to poor prognosis, sensitized embryos to MTH1 inhibition. Using a transgenic zebrafish line, in which the cellular redox status can be monitored in vivo, we detected an increase in oxidative pressure upon activation of hypoxic signaling. Pretreatment with the antioxidant N-acetyl-L-cysteine protected embryos with activated hypoxia signaling against MTH1 inhibition, suggesting that the aberrant redox environment likely causes sensitization. In summary, MTH1 inhibition may offer a general approach to treat cancers characterized by deregulated hypoxia signaling or redox imbalance. Cancer Res; 76(8); 2366-75. ©2016 AACR.

PubMed: 26862114
DOI: 10.1158/0008-5472.CAN-15-2380

Experimental method

X-RAY DIFFRACTION (1.9 Å)