4N1U

Structure of human MTH1 in complex with TH588

Summary for 4N1U

• Entry DOI: 10.2210/pdb4n1u/pdb
• Related: 3ZR0 3ZR1 4N1T
• Descriptor: 7,8-dihydro-8-oxoguanine triphosphatase, N~4~-cyclopropyl-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine, SULFATE ION, ... (4 entities in total)
• Functional Keywords: oxidised nucleotide degradation, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Isoform p18: Cytoplasm. Isoform p26: Cytoplasm: P36639
• Total number of polymer chains: 2
• Total formula weight: 38052.30

Authors

Berntsson, R.P.-A.,Jemth, A.,Gustafsson, R.,Svensson, L.M.,Helleday, T.,Stenmark, P. (deposition date: 2013-10-04, release date: 2014-04-16, Last modification date: 2023-09-20)

Primary citation

Gad, H.,Koolmeister, T.,Jemth, A.S.,Eshtad, S.,Jacques, S.A.,Strom, C.E.,Svensson, L.M.,Schultz, N.,Lundback, T.,Einarsdottir, B.O.,Saleh, A.,Gokturk, C.,Baranczewski, P.,Svensson, R.,Berntsson, R.P.,Gustafsson, R.,Stromberg, K.,Sanjiv, K.,Jacques-Cordonnier, M.C.,Desroses, M.,Gustavsson, A.L.,Olofsson, R.,Johansson, F.,Homan, E.J.,Loseva, O.,Brautigam, L.,Johansson, L.,Hoglund, A.,Hagenkort, A.,Pham, T.,Altun, M.,Gaugaz, F.Z.,Vikingsson, S.,Evers, B.,Henriksson, M.,Vallin, K.S.,Wallner, O.A.,Hammarstrom, L.G.,Wiita, E.,Almlof, I.,Kalderen, C.,Axelsson, H.,Djureinovic, T.,Puigvert, J.C.,Haggblad, M.,Jeppsson, F.,Martens, U.,Lundin, C.,Lundgren, B.,Granelli, I.,Jensen, A.J.,Artursson, P.,Nilsson, J.A.,Stenmark, P.,Scobie, M.,Berglund, U.W.,Helleday, T.
MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool.
Nature, 508:215-221, 2014

PubMed Abstract: Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bind in the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.

PubMed: 24695224
DOI: 10.1038/nature13181

Experimental method

X-RAY DIFFRACTION (1.6 Å)