9FNV

Structure of the mouse 8-oxoguanine DNA Glycosylase mOGG1 in complex with ligand TH12163

これはPDB形式変換不可エントリーです。

9FNV の概要

• エントリーDOI: 10.2210/pdb9fnv/pdb
• 分子名称: N-glycosylase/DNA lyase, 2-(2-pyridin-3-yl-1~{H}-indol-3-yl)ethanamine, NICKEL (II) ION, ... (4 entities in total)
• 機能のキーワード: complex, dna binding protein
• 由来する生物種: Mus musculus (house mouse)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 108220.55

構造登録者

Scaletti, E.,Stenmark, P. (登録日: 2024-06-11, 公開日: 2025-06-25, 最終更新日: 2025-11-26)

主引用文献

Varga, M.,Ortis, F.,Del Prado, A.,Eddershaw, A.,Scaletti Hutchinson, E.,Hank, E.C.,Zhou, K.,Rudolfova, N.,Dodaro, A.,Wiita, E.,Almlof, I.,Karsten, S.,Mamonov, K.,Ahmed, S.H.,Bentley, K.,Wallner, O.,Homan, E.J.,Scobie, M.,Helleday, T.,Prejano, M.,Stenmark, P.,de Vega, M.,Watson, A.J.B.,Michel, M.
Giving an Enzyme Scissors: Serotonin Derivatives as Potent Organocatalytic Switches for DNA Repair Enzyme OGG1.
J.Med.Chem., 68:22455-22483, 2025

PubMed Abstract: The base excision repair enzyme 8-oxoguanine DNA glycosylase 1 (OGG1) plays a central role in maintaining genome integrity and mediating cellular responses to oxidative stress. As such, it represents an attractive target for pharmaceutical modulation. Small-molecule organocatalytic switches (ORCAs) greatly enhance the rate of OGG1-catalyzed cleavage of DNA abasic sites, thereby accelerating DNA repair. Here, we present the discovery and hit-to-lead optimization of a novel class of highly potent serotonin-derived ORCAs with greatly improved pharmacokinetic properties. Biochemical assays, X-ray crystallography, and molecular dynamics simulations point toward a water-mediated mechanism of activation, distinct from previously proposed Brønsted base-assisted models. These findings establish serotonin-based ORCAs as promising chemical probes and potential leads for therapeutic modulation of OGG1 in oxidative stress-driven diseases.

PubMed: 41092057
DOI: 10.1021/acs.jmedchem.5c01454

実験手法

X-RAY DIFFRACTION (2.25 Å)