6g40 | pdb_00006g40

Structure of the mouse 8-oxoguanine DNA Glycosylase mOGG1 in complex with ligand TH9525

spinqualitylabelsall models 6g40, resolution 2.49Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6g40 is a 3 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ACT, ELK, NI, PEG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function OGG1_MOUSE DNA repair enzyme that incises DNA at 8-oxoG residues. Excises 7,8-dihydro-8-oxoguanine and 2,6-diamino-4-hydroxy-5-N-methylformamidopyrimidine (FAPY) from damaged DNA. Has a beta-lyase activity that nicks DNA 3' to the lesion. Publication Abstract from PubMed 8-oxo Guanine DNA Glycosylase 1 is the initiating enzyme within base excision repair and removes oxidized guanines from damaged DNA. Since unrepaired 8-oxoG could lead to G : C-->T : A transversion, base removal is of utmost importance for cells to ensure genomic integrity. For cells with elevated levels of reactive oxygen species this dependency is further increased. In the past we and others have validated OGG1 as a target for inhibitors to treat cancer and inflammation. Here, we present the optimization campaign that led to the broadly used tool compound TH5487. Based on results from a small molecule screening campaign, we performed hit to lead expansion and arrived at potent and selective substituted N-piperidinyl-benzimidazolones. Using X-ray crystallography data, we describe the surprising binding mode of the most potent member of the class, TH8535. Here, the N-Piperidinyl-linker adopts a chair instead of a boat conformation which was found for weaker analogues. We further demonstrate cellular target engagement and efficacy of TH8535 against a number of cancer cell lines. Optimization of N-Piperidinyl-Benzimidazolone Derivatives as Potent and Selective Inhibitors of 8-Oxo-Guanine DNA Glycosylase 1.,Wallner O, Cazares-Korner A, Scaletti ER, Masuyer G, Bekkhus T, Visnes T, Mamonov K, Ortis F, Lundback T, Volkova M, Koolmeister T, Wiita E, Loseva O, Pandey M, Homan E, Benitez-Buelga C, Davies J, Scobie M, Warpman Berglund U, Kalderen C, Stenmark P, Helleday T, Michel M ChemMedChem. 2023 Jan 3;18(1):e202200310. doi: 10.1002/cmdc.202200310. Epub 2022 , Oct 13. PMID:36128847 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also DNA glycosylase 3D structures

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