6G3Y

Structure of the mouse 8-oxoguanine DNA Glycosylase mOGG1 in complex with ligand TH5675

Summary for 6G3Y

• Entry DOI: 10.2210/pdb6g3y/pdb
• Descriptor: N-glycosylase/DNA lyase, 4-(4-azanyl-2-oxidanylidene-3~{H}-benzimidazol-1-yl)-~{N}-(4-iodophenyl)piperidine-1-carboxamide, NICKEL (II) ION, ... (5 entities in total)
• Functional Keywords: n-glycosylase, dna lyase, dna binding protein
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 3
• Total formula weight: 108999.59

Authors

Masuyer, G.,Helleday, T.,Stenmark, P. (deposition date: 2018-03-26, release date: 2018-11-28, Last modification date: 2024-01-17)

Primary citation

Visnes, T.,Cazares-Korner, A.,Hao, W.,Wallner, O.,Masuyer, G.,Loseva, O.,Mortusewicz, O.,Wiita, E.,Sarno, A.,Manoilov, A.,Astorga-Wells, J.,Jemth, A.S.,Pan, L.,Sanjiv, K.,Karsten, S.,Gokturk, C.,Grube, M.,Homan, E.J.,Hanna, B.M.F.,Paulin, C.B.J.,Pham, T.,Rasti, A.,Berglund, U.W.,von Nicolai, C.,Benitez-Buelga, C.,Koolmeister, T.,Ivanic, D.,Iliev, P.,Scobie, M.,Krokan, H.E.,Baranczewski, P.,Artursson, P.,Altun, M.,Jensen, A.J.,Kalderen, C.,Ba, X.,Zubarev, R.A.,Stenmark, P.,Boldogh, I.,Helleday, T.
Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation.
Science, 362:834-839, 2018

PubMed Abstract: The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG and because -deficient mice are resistant to acute and systemic inflammation, we hypothesized that OGG1 inhibition may represent a strategy for the prevention and treatment of inflammation. We developed TH5487, a selective active-site inhibitor of OGG1, which hampers OGG1 binding to and repair of 8-oxoG and which is well tolerated by mice. TH5487 prevents tumor necrosis factor-α-induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor κB and proinflammatory gene expression, resulting in decreased immune cell recruitment to mouse lungs. Thus, we present a proof of concept that targeting oxidative DNA repair can alleviate inflammatory conditions in vivo.

PubMed: 30442810
DOI: 10.1126/science.aar8048

Experimental method

X-RAY DIFFRACTION (2.51 Å)