7AYY

Structure of the human 8-oxoguanine DNA Glycosylase hOGG1 in complex with activator TH10785

This is a non-PDB format compatible entry.

Summary for 7AYY

• Entry DOI: 10.2210/pdb7ayy/pdb
• Descriptor: N-glycosylase/DNA lyase, ~{N}-cyclohexyl-2-cyclopropyl-quinazolin-4-amine, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (5 entities in total)
• Functional Keywords: 8-oxoguanine dna glycosylase, n-glycosylase, dna lyase, dna repair, dna binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 5
• Total formula weight: 191716.14

Authors

Masuyer, G.,Davies, J.R.,Stenmark, P. (deposition date: 2020-11-13, release date: 2022-06-01, Last modification date: 2024-01-31)

Primary citation

Michel, M.,Benitez-Buelga, C.,Calvo, P.A.,Hanna, B.M.F.,Mortusewicz, O.,Masuyer, G.,Davies, J.,Wallner, O.,Sanjiv, K.,Albers, J.J.,Castaneda-Zegarra, S.,Jemth, A.S.,Visnes, T.,Sastre-Perona, A.,Danda, A.N.,Homan, E.J.,Marimuthu, K.,Zhenjun, Z.,Chi, C.N.,Sarno, A.,Wiita, E.,von Nicolai, C.,Komor, A.J.,Rajagopal, V.,Muller, S.,Hank, E.C.,Varga, M.,Scaletti, E.R.,Pandey, M.,Karsten, S.,Haslene-Hox, H.,Loevenich, S.,Marttila, P.,Rasti, A.,Mamonov, K.,Ortis, F.,Schomberg, F.,Loseva, O.,Stewart, J.,D'Arcy-Evans, N.,Koolmeister, T.,Henriksson, M.,Michel, D.,de Ory, A.,Acero, L.,Calvete, O.,Scobie, M.,Hertweck, C.,Vilotijevic, I.,Kalderen, C.,Osorio, A.,Perona, R.,Stolz, A.,Stenmark, P.,Berglund, U.W.,de Vega, M.,Helleday, T.
Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function.
Science, 376:1471-1476, 2022

PubMed Abstract: Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed β,δ-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging.

PubMed: 35737787
DOI: 10.1126/science.abf8980

Experimental method

X-RAY DIFFRACTION (2 Å)