9HLF
Structure of the mouse 8-oxoguanine DNA Glycosylase mOGG1 in complex with ligand TH14445
This is a non-PDB format compatible entry.
Summary for 9HLF
| Entry DOI | 10.2210/pdb9hlf/pdb |
| Descriptor | N-glycosylase/DNA lyase, ~{N}-(3,4-dichlorophenyl)pyridin-4-amine, PHOSPHATE ION, ... (6 entities in total) |
| Functional Keywords | ogg1, dna binding protein |
| Biological source | Mus musculus (house mouse) |
| Total number of polymer chains | 3 |
| Total formula weight | 107938.78 |
| Authors | |
| Primary citation | Kehler, M.,Zhou, K.,Kemas, A.M.,Del Prado, A.,Hutchinson, E.S.,Nairn, E.H.,Varga, M.,Plattner, Y.,Zhong, Y.,Purewal-Sidhu, O.,Haslam, J.,Wiita, E.,Gildie, H.,Singerova, K.,Szaruga, Z.,Almlof, I.,Hormann, F.M.,Liu, K.C.,Wallner, O.,Ortis, F.,Homan, E.J.,Gileadi, O.,Rudd, S.G.,Stenmark, P.,de Vega, M.,Helleday, T.,D'Arcy-Evans, N.D.,Lauschke, V.M.,Michel, M. Organocatalytic switches of DNA glycosylase OGG1 catalyze a highly efficient AP-lyase function. Chemistry, :e202500382-e202500382, 2025 Cited by PubMed Abstract: 8-oxoGuanine DNA glycosylase 1 (OGG1) is the first known target of organocatalytic switches (ORCAs), which rewrite the biochemical function of the enzyme through redirection of its preferred substrate from 8-oxoG to AP sites. Previously, different ORCA chemotypes were shown to enhance the operational pH window for OGG1, possibly through direct involvement in proton transfer events during DNA strand cleavage. Accordingly, compound pK is a crucial and necessary consideration for the identification and application of future OGG1 ORCAs. Here, we identify a minimal structure of organocatalytic switches-4-anilino pyridines and 6-anilino pyrimidines-which are dimethyl-amino-pyridine (DMAP)-type Brønsted bases binding the active site of OGG1. Systematic interrogation of compound basicity through modulation of electron-withdrawing (EWG) and electron-donating (EDG) substituents reveals that a pK less or equal to the assay pH is a viable parameter for prediction of compound activity. The lead structure (AC 13 nM, pK 7.0) was then identified as a potent scaffold from a screen in a patient-derived 3D model of metabolic dysfunction-associated steatohepatitis (MASH), where it reduced hepatic fibrosis by 35%. Collectively, these findings deepen the knowledge of this novel modulator class, with important implications for future enzyme targets and probe development. PubMed: 40294343DOI: 10.1002/chem.202500382 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.64 Å) |
Structure validation
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