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==Crystal structure of human thymine DNA glycosylase TDG in complex with a covalent inhibitor (1S, 5R)-C-2711==
<StructureSection load='9lhp' size='340' side='right'caption='[[9lhp]], [[Resolution|resolution]] 2.14&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9lhp]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9LHP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9LHP FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.14&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1LYG:(1~{S},2~{S})-2-[(2-methoxy-5-methyl-4-oxidanyl-phenyl)methyl]cyclopropane-1-carboxylic+acid'>A1LYG</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=9lhp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9lhp OCA], [https://pdbe.org/9lhp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9lhp RCSB], [https://www.ebi.ac.uk/pdbsum/9lhp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9lhp ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Thymine DNA glycosylase (TDG) is a multifaceted protein involved in base-excision repair, DNA demethylation and transcriptional regulation, with key roles in embryonic development and tumorigenesis. However, the mechanisms underlying its role in cancer progression and the therapeutic applications targeting TDG remain largely unknown. Here we demonstrate that targeting TDG induces synthetic lethality in p53-deficient cancers. We developed C-271, a first-in-class, small-molecule inhibitor that covalently binds to TDG, disrupting its DNA-binding capability. C-271 exhibits potent therapeutic efficacy in suppressing p53-deficient tumors. Mechanistically, TDG and p53 redundantly promote the transcription of DHX9, an RNA helicase that resolves double-stranded RNA (dsRNA). TDG inhibition in p53-deficient cancer cells leads to DHX9 downregulation and, thus, aberrant dsRNA accumulation, which activates the RIG-I/MDA5-MAVS sensing pathway, resulting in tumor suppression and enhanced antitumor immunity. These findings highlight the synthetic lethality between TDG and p53, positioning TDG inhibition as a promising therapeutic strategy for p53-deficient cancers.

Targeting thymine DNA glycosylase induces synthetic lethality in p53-deficient cancers.,Zhou JX, Shao ZY, Zhang L, Guo JN, Wang M, Xu Q, Wang YQ, Xu Q, Zhou D, Ren SX, Yu YH, Lu ZH, Pang GZ, Cao Y, Liu YL, Zhou B, Ji HB, Chen YH, Wu HP, Xu GL, Zhang L, Du YR Nat Chem Biol. 2026 Jan 22. doi: 10.1038/s41589-025-02100-1. PMID:41571914<ref>PMID:41571914</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9lhp" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Du YR]]
[[Category: Guo JN]]
[[Category: Shao ZY]]
[[Category: Wu HP]]
[[Category: Xu GL]]
[[Category: Zhang L]]
[[Category: Zhou JX]]