6RNM

Crystal structure of a complex between the LlFpg protein, a THF-DNA and an inhibitor

6RNM の概要

• エントリーDOI: 10.2210/pdb6rnm/pdb
• 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'), ... (7 entities in total)
• 機能のキーワード: dna glycosylase complex, inhibitor, hydrolase
• 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: 39943.50

構造登録者

Coste, F.,Goffinont, S.,Castaing, B. (登録日: 2019-05-09, 公開日: 2020-04-15, 最終更新日: 2024-01-24)

主引用文献

Rieux, C.,Goffinont, S.,Coste, F.,Tber, Z.,Cros, J.,Roy, V.,Guerin, M.,Gaudon, V.,Bourg, S.,Biela, A.,Aucagne, V.,Agrofoglio, L.,Garnier, N.,Castaing, B.
Thiopurine Derivative-Induced Fpg/Nei DNA Glycosylase Inhibition: Structural, Dynamic and Functional Insights.
Int J Mol Sci, 21:-, 2020

PubMed Abstract: DNA glycosylases are emerging as relevant pharmacological targets in inflammation, cancer and neurodegenerative diseases. Consequently, the search for inhibitors of these enzymes has become a very active research field. As a continuation of previous work that showed that 2-thioxanthine (2TX) is an irreversible inhibitor of zinc finger (ZnF)-containing Fpg/Nei DNA glycosylases, we designed and synthesized a mini-library of 2TX-derivatives (TXn) and evaluated their ability to inhibit Fpg/Nei enzymes. Among forty compounds, four TXn were better inhibitors than 2TX for Fpg. Unexpectedly, but very interestingly, two dithiolated derivatives more selectively and efficiently inhibit the zincless finger (ZnLF)-containing enzymes (human and mimivirus Neil1 DNA glycosylases hNeil1 and MvNei1, respectively). By combining chemistry, biochemistry, mass spectrometry, blind and flexible docking and X-ray structure analysis, we localized new TXn binding sites on Fpg/Nei enzymes. This endeavor allowed us to decipher at the atomic level the mode of action for the best TXn inhibitors on the ZnF-containing enzymes. We discovered an original inhibition mechanism for the ZnLF-containing Fpg/Nei DNA glycosylases by disulfide cyclic trimeric forms of dithiopurines. This work paves the way for the design and synthesis of a new structural class of inhibitors for selective pharmacological targeting of hNeil1 in cancer and neurodegenerative diseases.

PubMed: 32192183
DOI: 10.3390/ijms21062058

実験手法

X-RAY DIFFRACTION (1.76 Å)