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| | ==Crystal structure of a complex between an inhibited LlFpg and a N7-Benzyl-Fapy-dG containing DNA== | | ==Crystal structure of a complex between an inhibited LlFpg and a N7-Benzyl-Fapy-dG containing DNA== |
| - | <StructureSection load='4pdi' size='340' side='right' caption='[[4pdi]], [[Resolution|resolution]] 2.10Å' scene=''> | + | <StructureSection load='4pdi' size='340' side='right'caption='[[4pdi]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4pdi]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PDI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4PDI FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4pdi]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Lactococcus_cremoris Lactococcus cremoris] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PDI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4PDI FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2ON:2-SULFANYL-1,9-DIHYDRO-6H-PURIN-6-ONE'>2ON</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SOS:[(1R,2S,4R)-4-({2-AMINO-5-[BENZYL(FORMYL)AMINO]-6-OXO-1,6-DIHYDROPYRIMIDIN-4-YL}AMINO)-2-HYDROXYCYCLOPENTYL]METHYL+DIHYDROGEN+PHOSPHATE'>SOS</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2ON:2-SULFANYL-1,9-DIHYDRO-6H-PURIN-6-ONE'>2ON</scene>, <scene name='pdbligand=SOS:[(1R,2S,4R)-4-({2-AMINO-5-[BENZYL(FORMYL)AMINO]-6-OXO-1,6-DIHYDROPYRIMIDIN-4-YL}AMINO)-2-HYDROXYCYCLOPENTYL]METHYL+DIHYDROGEN+PHOSPHATE'>SOS</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4pcz|4pcz]], [[4pd2|4pd2]], [[4pdg|4pdg]]</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4pdi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pdi OCA], [https://pdbe.org/4pdi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4pdi RCSB], [https://www.ebi.ac.uk/pdbsum/4pdi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4pdi ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/DNA-formamidopyrimidine_glycosylase DNA-formamidopyrimidine glycosylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.2.23 3.2.2.23] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4pdi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pdi OCA], [http://pdbe.org/4pdi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4pdi RCSB], [http://www.ebi.ac.uk/pdbsum/4pdi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4pdi ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/FPG_LACLC FPG_LACLC]] Involved in base excision repair of DNA damaged by oxidation or by mutagenic agents. Acts as DNA glycosylase that recognizes and removes damaged bases. Has a preference for oxidized purines, such as 7,8-dihydro-8-oxoguanine (8-oxoG). Has AP (apurinic/apyrimidinic) lyase activity and introduces nicks in the DNA strand. Cleaves the DNA backbone by beta-delta elimination to generate a single-strand break at the site of the removed base with both 3'- and 5'-phosphates.<ref>PMID:7704272</ref> | + | [https://www.uniprot.org/uniprot/FPG_LACLC FPG_LACLC] Involved in base excision repair of DNA damaged by oxidation or by mutagenic agents. Acts as DNA glycosylase that recognizes and removes damaged bases. Has a preference for oxidized purines, such as 7,8-dihydro-8-oxoguanine (8-oxoG). Has AP (apurinic/apyrimidinic) lyase activity and introduces nicks in the DNA strand. Cleaves the DNA backbone by beta-delta elimination to generate a single-strand break at the site of the removed base with both 3'- and 5'-phosphates.<ref>PMID:7704272</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4pdi" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4pdi" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[DNA glycosylase 3D structures|DNA glycosylase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: DNA-formamidopyrimidine glycosylase]] | + | [[Category: Lactococcus cremoris]] |
| - | [[Category: Castaing, B]] | + | [[Category: Large Structures]] |
| - | [[Category: Coste, F]] | + | [[Category: Synthetic construct]] |
| - | [[Category: 2tx inhibitor]] | + | [[Category: Castaing B]] |
| - | [[Category: Dna glycosylase]] | + | [[Category: Coste F]] |
| - | [[Category: Hydrolase-dna complex]]
| + | |
| Structural highlights
Function
FPG_LACLC Involved in base excision repair of DNA damaged by oxidation or by mutagenic agents. Acts as DNA glycosylase that recognizes and removes damaged bases. Has a preference for oxidized purines, such as 7,8-dihydro-8-oxoguanine (8-oxoG). Has AP (apurinic/apyrimidinic) lyase activity and introduces nicks in the DNA strand. Cleaves the DNA backbone by beta-delta elimination to generate a single-strand break at the site of the removed base with both 3'- and 5'-phosphates.[1]
Publication Abstract from PubMed
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.
Zinc finger oxidation of Fpg/Nei DNA glycosylases by 2-thioxanthine: biochemical and X-ray structural characterization.,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 Nucleic Acids Res. 2014;42(16):10748-61. doi: 10.1093/nar/gku613. Epub 2014 Aug, 20. PMID:25143530[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Duwat P, de Oliveira R, Ehrlich SD, Boiteux S. Repair of oxidative DNA damage in gram-positive bacteria: the Lactococcus lactis Fpg protein. Microbiology. 1995 Feb;141 ( Pt 2):411-7. PMID:7704272
- ↑ 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. 2014;42(16):10748-61. doi: 10.1093/nar/gku613. Epub 2014 Aug, 20. PMID:25143530 doi:http://dx.doi.org/10.1093/nar/gku613
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