4PCZ

Crystal structure of a complex between R247G LlFPG mutant and a THF containing DNA

4PCZ の概要

• エントリーDOI: 10.2210/pdb4pcz/pdb
• 関連するPDBエントリー: 4PD2 4PDG 4PDI
• 分子名称: Formamidopyrimidine-DNA glycosylase, DNA (5'-D(*CP*TP*CP*TP*TP*TP*(3DR)P*TP*TP*TP*CP*TP*CP*G)-3'), DNA (5'-D(*GP*CP*GP*AP*GP*AP*AP*AP*CP*AP*AP*AP*GP*A)-3'), ... (6 entities in total)
• 機能のキーワード: dna glycosylase, thf, hydrolase-dna complex, hydrolase/dna
• 由来する生物種: Lactococcus lactis subsp. cremoris; 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 39584.07

構造登録者

Coste, F.,Castaing, B. (登録日: 2014-04-17, 公開日: 2015-04-01, 最終更新日: 2023-09-27)

主引用文献

Biela, A.,Coste, F.,Culard, F.,Guerin, M.,Goffinont, S.,Gasteiger, K.,Ciesla, J.,Winczura, A.,Kazimierczuk, Z.,Gasparutto, D.,Carell, T.,Tudek, B.,Castaing, B.
Zinc finger oxidation of Fpg/Nei DNA glycosylases by 2-thioxanthine: biochemical and X-ray structural characterization.
Nucleic Acids Res., 42:10748-10761, 2014

PubMed Abstract: DNA glycosylases from the Fpg/Nei structural superfamily are base excision repair enzymes involved in the removal of a wide variety of mutagen and potentially lethal oxidized purines and pyrimidines. Although involved in genome stability, the recent discovery of synthetic lethal relationships between DNA glycosylases and other pathways highlights the potential of DNA glycosylase inhibitors for future medicinal chemistry development in cancer therapy. By combining biochemical and structural approaches, the physical target of 2-thioxanthine (2TX), an uncompetitive inhibitor of Fpg, was identified. 2TX interacts with the zinc finger (ZnF) DNA binding domain of the enzyme. This explains why the zincless hNEIL1 enzyme is resistant to 2TX. Crystal structures of the enzyme bound to DNA in the presence of 2TX demonstrate that the inhibitor chemically reacts with cysteine thiolates of ZnF and induces the loss of zinc. The molecular mechanism by which 2TX inhibits Fpg may be generalized to all prokaryote and eukaryote ZnF-containing Fpg/Nei-DNA glycosylases. Cell experiments show that 2TX can operate in cellulo on the human Fpg/Nei DNA glycosylases. The atomic elucidation of the determinants for the interaction of 2TX to Fpg provides the foundation for the future design and synthesis of new inhibitors with high efficiency and selectivity.

PubMed: 25143530
DOI: 10.1093/nar/gku613

実験手法

X-RAY DIFFRACTION (1.7 Å)