6rnr: Difference between revisions
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==The crystal structure of a complex between the LlFpg protein, a THF-DNA and an inhibitor== | ==The crystal structure of a complex between the LlFpg protein, a THF-DNA and an inhibitor== | ||
<StructureSection load='6rnr' size='340' side='right'caption='[[6rnr]]' scene=''> | <StructureSection load='6rnr' size='340' side='right'caption='[[6rnr]], [[Resolution|resolution]] 2.00Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RNR OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6rnr]] 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=6RNR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6RNR FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.003Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3DR:1,2-DIDEOXYRIBOFURANOSE-5-PHOSPHATE'>3DR</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=KBN:2-(trifluoromethyl)-9~{H}-purine-6-thiol'>KBN</scene></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=6rnr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rnr OCA], [https://pdbe.org/6rnr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6rnr RCSB], [https://www.ebi.ac.uk/pdbsum/6rnr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6rnr ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[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;"> | |||
== Publication Abstract from PubMed == | |||
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. | |||
Thiopurine Derivative-Induced Fpg/Nei DNA Glycosylase Inhibition: Structural, Dynamic and Functional Insights.,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 Int J Mol Sci. 2020 Mar 17;21(6). pii: ijms21062058. doi: 10.3390/ijms21062058. PMID:32192183<ref>PMID:32192183</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6rnr" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[DNA glycosylase 3D structures|DNA glycosylase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Lactococcus cremoris]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Synthetic construct]] | |||
[[Category: Castaing B]] | [[Category: Castaing B]] | ||
[[Category: Coste F]] | [[Category: Coste F]] | ||
[[Category: Goffinont S]] | [[Category: Goffinont S]] | ||