6RO2

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

Summary for 6RO2

• Entry DOI: 10.2210/pdb6ro2/pdb
• Descriptor: 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)
• Functional Keywords: dna glycosylase complex, inhibitor, hydrolase
• Biological source: Lactococcus lactis subsp. cremoris; More
• Total number of polymer chains: 3
• Total formula weight: 40123.34

Authors

Coste, F.,Goffinont, S.,Castaing, B. (deposition date: 2019-05-10, release date: 2020-04-15, Last modification date: 2024-10-23)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.821 Å)