7PZ1
Structure of the mouse 8-oxoguanine DNA Glycosylase mOGG1 in complex with ligand TH8535
This is a non-PDB format compatible entry.
Summary for 7PZ1
| Entry DOI | 10.2210/pdb7pz1/pdb |
| Descriptor | N-glycosylase/DNA lyase, 4-(4-bromanyl-2-oxidanylidene-3~{H}-benzimidazol-1-yl)-~{N}-(3-methoxy-4-methyl-phenyl)piperidine-1-carboxamide, NICKEL (II) ION, ... (6 entities in total) |
| Functional Keywords | glycosylase, dna binding protein |
| Biological source | Mus musculus (Mouse) |
| Total number of polymer chains | 3 |
| Total formula weight | 108122.15 |
| Authors | Scaletti, E.R.,Helleday, T.,Stenmark, P. (deposition date: 2021-10-11, release date: 2022-11-02, Last modification date: 2024-02-07) |
| Primary citation | Wallner, O.,Cazares-Korner, A.,Scaletti, E.R.,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. Optimization of N-Piperidinyl-Benzimidazolone Derivatives as Potent and Selective Inhibitors of 8-Oxo-Guanine DNA Glycosylase 1. Chemmedchem, 18:e202200310-e202200310, 2023 Cited by PubMed Abstract: 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. PubMed: 36128847DOI: 10.1002/cmdc.202200310 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.45 Å) |
Structure validation
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