Target Information
| Target General Information | Top | |||||
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| Target ID |
T91681
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| Target Name |
Thymine-DNA glycosylase (TDG)
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| Synonyms |
hTDG
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| Gene Name |
TDG
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| Target Type |
Literature-reported target
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[1] | ||||
| Function |
DNA glycosylase that plays a key role in active DNA demethylation: specifically recognizes and binds 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) in the context of CpG sites and mediates their excision through base-excision repair (BER) to install an unmethylated cytosine. Cannot remove 5-hydroxymethylcytosine (5hmC). According to an alternative model, involved in DNA demethylation by mediating DNA glycolase activity toward 5-hydroxymethyluracil (5hmU) produced by deamination of 5hmC. Also involved in DNA repair by acting as a thymine-DNA glycosylase that mediates correction of G/T mispairs to G/C pairs: in the DNA of higher eukaryotes, hydrolytic deamination of 5-methylcytosine to thymine leads to the formation of G/T mismatches. Its role in the repair of canonical base damage is however minor compared to its role in DNA demethylation. It is capable of hydrolyzing the carbon-nitrogen bond between the sugar-phosphate backbone of the DNA and a mispaired thymine. In addition to the G/T, it can remove thymine also from C/T and T/T mispairs in the order G/T >> C/T > T/T. It has no detectable activity on apyrimidinic sites and does not catalyze the removal of thymine from A/T pairs or from single-stranded DNA. It can also remove uracil and 5-bromouracil from mispairs with guanine.
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| BioChemical Class |
Uracil-DNA glycosylase (UDG) superfamily. TDG/mug family
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| UniProt ID | ||||||
| EC Number |
EC 3.2.2.29
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| Sequence |
MEAENAGSYSLQQAQAFYTFPFQQLMAEAPNMAVVNEQQMPEEVPAPAPAQEPVQEAPKG
RKRKPRTTEPKQPVEPKKPVESKKSGKSAKSKEKQEKITDTFKVKRKVDRFNGVSEAELL TKTLPDILTFNLDIVIIGINPGLMAAYKGHHYPGPGNHFWKCLFMSGLSEVQLNHMDDHT LPGKYGIGFTNMVERTTPGSKDLSSKEFREGGRILVQKLQKYQPRIAVFNGKCIYEIFSK EVFGVKVKNLEFGLQPHKIPDTETLCYVMPSSSARCAQFPRAQDKVHYYIKLKDLRDQLK GIERNMDVQEVQYTFDLQLAQEDAKKMAVKEEKYDPGYEAAYGGAYGENPCSSEPCGFSS NGLIESVELRGESAFSGIPNGQWMTQSFTDQIPSFSNHCGTQEQEEESHA Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: 5-Hydroxymethyluracil | Ligand Info | |||||
| Structure Description | Human TDG in a post-reactive complex with 5-hydroxymethyluracil (5hmU) | PDB:4FNC | ||||
| Method | X-ray diffraction | Resolution | 2.49 Å | Mutation | No | [2] |
| PDB Sequence |
SFNGVSEAEL
119 LTKTLPDILT129 FNLDIVIIGI139 NPGLMAAYKG149 HHYPGPGNHF159 WKCLFMSGLS 169 EVQLNHMDDH179 TLPGKYGIGF189 TNMVERTTPG199 SKDLSSKEFR209 EGGRILVQKL 219 QKYQPRIAVF229 NGKCIYEIFS239 KEVFGVKVKN249 LEFGLQPHKI259 PDTETLCYVM 269 PSSSARCAQF279 PRAQDKVHYY289 IKLKDLRDQL299 KGIERN
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| Ligand Name: Deoxyribose 5-phosphate | Ligand Info | |||||
| Structure Description | Human TDG in a post-reactive complex with 5-hydroxymethyluracil (5hmU) | PDB:4FNC | ||||
| Method | X-ray diffraction | Resolution | 2.49 Å | Mutation | No | [2] |
| PDB Sequence |
SFNGVSEAEL
119 LTKTLPDILT129 FNLDIVIIGI139 NPGLMAAYKG149 HHYPGPGNHF159 WKCLFMSGLS 169 EVQLNHMDDH179 TLPGKYGIGF189 TNMVERTTPG199 SKDLSSKEFR209 EGGRILVQKL 219 QKYQPRIAVF229 NGKCIYEIFS239 KEVFGVKVKN249 LEFGLQPHKI259 PDTETLCYVM 269 PSSSARCAQF279 PRAQDKVHYY289 IKLKDLRDQL299 KGIERN
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Base excision repair | hsa03410 | Affiliated Target |
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| Class: Genetic Information Processing => Replication and repair | Pathway Hierarchy | ||
| Degree | 6 | Degree centrality | 6.45E-04 | Betweenness centrality | 6.38E-06 |
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| Closeness centrality | 2.24E-01 | Radiality | 1.39E+01 | Clustering coefficient | 2.67E-01 |
| Neighborhood connectivity | 4.55E+01 | Topological coefficient | 2.45E-01 | Eccentricity | 11 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Target Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Base excision repair | |||||
| References | Top | |||||
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| REF 1 | Mismatch-specific thymine DNA glycosylase and DNA polymerase beta mediate the correction of G.T mispairs in nuclear extracts from human cells. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5842-5. | |||||
| REF 2 | Excision of 5-hydroxymethyluracil and 5-carboxylcytosine by the thymine DNA glycosylase domain: its structural basis and implications for active DNA demethylation. Nucleic Acids Res. 2012 Nov 1;40(20):10203-14. | |||||
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