4n1u | pdb_00004n1u

Struture of human MTH1 in complex with TH588

spinqualitylabelsall models 4n1u, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4n1u is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 2GE, SO4 Related: 3zr0, 3zr1, 4n1t Gene: NUDT1, MTH1 (HUMAN) Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed 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. MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool.,Gad H, Koolmeister T, Jemth AS, Eshtad S, Jacques SA, Strom CE, Svensson LM, Schultz N, Lundback T, Einarsdottir BO, Saleh A, Gokturk C, Baranczewski P, Svensson R, Berntsson RP, Gustafsson R, Stromberg K, Sanjiv K, Jacques-Cordonnier MC, Desroses M, Gustavsson AL, Olofsson R, Johansson F, Homan EJ, Loseva O, Brautigam L, Johansson L, Hoglund A, Hagenkort A, Pham T, Altun M, Gaugaz FZ, Vikingsson S, Evers B, Henriksson M, Vallin KS, Wallner OA, Hammarstrom LG, Wiita E, Almlof I, Kalderen C, Axelsson H, Djureinovic T, Puigvert JC, Haggblad M, Jeppsson F, Martens U, Lundin C, Lundgren B, Granelli I, Jensen AJ, Artursson P, Nilsson JA, Stenmark P, Scobie M, Berglund UW, Helleday T Nature. 2014 Apr 10;508(7495):215-21. doi: 10.1038/nature13181. Epub 2014 Apr 2. PMID:24695224 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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