6rlw | pdb_00006rlw

Structure of the human 8-oxoguanine DNA Glycosylase hOGG1 in complex with inhibitor TH5487

spinqualitylabelsall models 6rlw, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6rlw is a 5 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: K8Q Gene: OGG1, MMH, MUTM, OGH1 (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [OGG1_HUMAN] Defects in OGG1 may be a cause of renal cell carcinoma (RCC) [MIM:144700]. It is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. It is subclassified into clear cell renal carcinoma (non-papillary carcinoma), papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma with medullary carcinoma of the kidney, and unclassified renal cell carcinoma. Function [OGG1_HUMAN] 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 Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause S-phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g. PARP1, as potential targets for cancer treatment. Targeting OGG1 arrests cancer cell proliferation by inducing replication stress.,Visnes T, Benitez-Buelga C, Cazares-Korner A, Sanjiv K, Hanna BMF, Mortusewicz O, Rajagopal V, Albers JJ, Hagey DW, Bekkhus T, Eshtad S, Baquero JM, Masuyer G, Wallner O, Muller S, Pham T, Gokturk C, Rasti A, Suman S, Torres-Ruiz R, Sarno A, Wiita E, Homan EJ, Karsten S, Marimuthu K, Michel M, Koolmeister T, Scobie M, Loseva O, Almlof I, Unterlass JE, Pettke A, Bostrom J, Pandey M, Gad H, Herr P, Jemth AS, El Andaloussi S, Kalderen C, Rodriguez-Perales S, Benitez J, Krokan HE, Altun M, Stenmark P, Berglund UW, Helleday T Nucleic Acids Res. 2020 Dec 2;48(21):12234-12251. doi: 10.1093/nar/gkaa1048. PMID:33211885 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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