Summary information and primary citation
- PDB-id
-
6rp7;
DSSR-derived features in text and
JSON formats
- Class
- hydrolase
- Method
- X-ray (2.0 Å)
- Summary
- The crystal structure of a complex between the llfpg
protein, a thf-DNA and an inhibitor
- Reference
-
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 (2020): "Thiopurine
Derivative-Induced Fpg/Nei DNA Glycosylase Inhibition:
Structural, Dynamic and Functional Insights." Int
J Mol Sci, 21. doi: 10.3390/ijms21062058.
- 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.
