6t5j | pdb_00006t5j

Structure of NUDT15 in complex with inhibitor TH1760

spinqualitylabelsall models 6t5j, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6t5j is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.6Å Ligands: CL, MG, MKB Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function NUD15_HUMAN Mediates the hydrolysis of some nucleoside diphosphate derivatives. Can degrade 8-oxo-dGTP in vitro, suggesting that it may remove an oxidatively damaged form of guanine (7,8-dihydro-8-oxoguanine) from DNA and the nucleotide pool, thereby preventing misincorporation of 8-oxo-dGTP into DNA thus preventing A:T to C:G transversions. Its substrate specificity in vivo however remains unclear (By similarity). May have a role in DNA synthesis and cell cycle progression through the interaction with PCNA. Publication Abstract from PubMed The NUDIX hydrolase NUDT15 was originally implicated in sanitizing oxidized nucleotides, but was later shown to hydrolyze the active thiopurine metabolites, 6-thio-(d)GTP, thereby dictating the clinical response of this standard-of-care treatment for leukemia and inflammatory diseases. Nonetheless, its physiological roles remain elusive. Here, we sought to develop small-molecule NUDT15 inhibitors to elucidate its biological functions and potentially to improve NUDT15-dependent chemotherapeutics. Lead compound TH1760 demonstrated low-nanomolar biochemical potency through direct and specific binding into the NUDT15 catalytic pocket and engaged cellular NUDT15 in the low-micromolar range. We also employed thiopurine potentiation as a proxy functional readout and demonstrated that TH1760 sensitized cells to 6-thioguanine through enhanced accumulation of 6-thio-(d)GTP in nucleic acids. A biochemically validated, inactive structural analog, TH7285, confirmed that increased thiopurine toxicity takes place via direct NUDT15 inhibition. In conclusion, TH1760 represents the first chemical probe for interrogating NUDT15 biology and potential therapeutic avenues. Development of a chemical probe against NUDT15.,Zhang SM, Desroses M, Hagenkort A, Valerie NCK, Rehling D, Carter M, Wallner O, Koolmeister T, Throup A, Jemth AS, Almlof I, Loseva O, Lundback T, Axelsson H, Regmi S, Sarno A, Kramer A, Pudelko L, Brautigam L, Rasti A, Gottmann M, Wiita E, Kutzner J, Schaller T, Kalderen C, Cazares-Korner A, Page BDG, Krimpenfort R, Eshtad S, Altun M, Rudd SG, Knapp S, Scobie M, Homan EJ, Berglund UW, Stenmark P, Helleday T Nat Chem Biol. 2020 Jul 20. pii: 10.1038/s41589-020-0592-z. doi:, 10.1038/s41589-020-0592-z. PMID:32690945 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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