Target Information
Target General Information | Top | |||||
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Target ID |
T04696
(Former ID: TTDNR00765)
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Target Name |
Tyrosyl-DNA phosphodiesterase 2 (TDP2)
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Synonyms |
hTDP2; VPg unlinkase; Tyrosyl-RNA phosphodiesterase; Tyr-DNA phosphodiesterase 2; TRAF and TNF receptor-associated protein; TDP2; ETS1-associated protein II; ETS1-associated protein 2; EAPII; 5'-tyrosyl-DNA phosphodiesterase; 5'-Tyr-DNA phosphodiesterase
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Gene Name |
TDP2
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Target Type |
Literature-reported target
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[1] | ||||
Function |
DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 5'-phosphodiester bond, giving rise to DNA with a free 5' phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase 2 (TOP2) active site tyrosine residue. Hydrolyzes 5'- phosphoglycolates on protruding 5' ends on DNA double-strand breaks (DSBs) due to DNA damage by radiation and free radicals. The 5'-tyrosyl DNA phosphodiesterase activity can enable the repair of TOP2-induced DSBs without the need for nuclease activity, creating a 'clean' DSB with 5'-phosphate termini that are ready for ligation. Has preference for single-stranded DNA or duplex DNA with a 4 base pair overhang as substrate. Has also 3'- tyrosyl DNA phosphodiesterase activity, but less efficiently and much slower than TDP1. Constitutes the major if not only 5'- tyrosyl-DNA phosphodiesterase in cells. Also acts as a 5'-tyrosyl- RNA phosphodiesterase following picornavirus infection: its activity is hijacked by picornavirus and acts by specifically cleaving the protein-RNA covalent linkage generated during the viral genomic RNA replication steps of a picornavirus infection, without impairing the integrity of viral RNA. Also acts as an adapter by participating in the specific activation of MAP3K7/TAK1 in response to TGF-beta: associates with components of the TGF- beta receptor-TRAF6-TAK1 signaling module and promotes their ubiquitination dependent complex formation. Involved in non- canonical TGF-beta induced signaling routes. May also act as a negative regulator of ETS1 and may inhibit NF-kappa-B activation. Acts as a regulator of ribosome biogenesis following stress.
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BioChemical Class |
Phosphoric diester hydrolase
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UniProt ID | ||||||
EC Number |
EC 3.1.4.-
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Sequence |
MELGSCLEGGREAAEEEGEPEVKKRRLLCVEFASVASCDAAVAQCFLAENDWEMERALNS
YFEPPVEESALERRPETISEPKTYVDLTNEETTDSTTSKISPSEDTQQENGSMFSLITWN IDGLDLNNLSERARGVCSYLALYSPDVIFLQEVIPPYYSYLKKRSSNYEIITGHEEGYFT AIMLKKSRVKLKSQEIIPFPSTKMMRNLLCVHVNVSGNELCLMTSHLESTRGHAAERMNQ LKMVLKKMQEAPESATVIFAGDTNLRDREVTRCGGLPNNIVDVWEFLGKPKHCQYTWDTQ MNSNLGITAACKLRFDRIFFRAAAEEGHIIPRSLDLLGLEKLDCGRFPSDHWGLLCNLDI IL 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: 2,4-Dioxo-10-[3-(1h-Tetrazol-5-Yl)phenyl]-2,3,4,10-Tetrahydropyrimido[4,5-B]quinoline-8-Carbonitrile | Ligand Info | |||||
Structure Description | Crystal structure of the catalytic domain of human tyrosyl DNA phosphodiesterase 2 in complex with a small molecule inhibitor | PDB:5J3S | ||||
Method | X-ray diffraction | Resolution | 3.40 Å | Mutation | Yes | [2] |
PDB Sequence |
HMFSLITWNI
121 DGLDLNNLSE131 RARGVCSYLA141 LYSPDVIFLQ151 EVIPPYYSYL161 KKRSSNYEII 171 TGHEEGYFTA181 IMLKKSRVKL191 KSQEIIPFPS201 TKMMRNLLCV211 HVNVSGNELC 221 LMTSHLESTR231 GHAAERMNQL241 KMVLKKMQEA251 VIFAGDTNLR266 DREVTRSGGL 276 PNNIVDVWEF286 LGKPKHCQYT296 WDTQMNSNLG306 ITAACKLRFD316 RIFFRIIPRS 331 LDLLGLEKLD341 CGRFPSDHWG351 LLCNLD
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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 Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
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 Tissue Distribution
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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Degree | 1 | Degree centrality | 1.07E-04 | Betweenness centrality | 0.00E+00 |
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Closeness centrality | 1.95E-01 | Radiality | 1.34E+01 | Clustering coefficient | 0.00E+00 |
Neighborhood connectivity | 2.90E+01 | Topological coefficient | 1.00E+00 | Eccentricity | 12 |
Download | Click to Download the Full PPI Network of This Target | ||||
Chemical Structure based Activity Landscape of Target | Top |
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Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
References | Top | |||||
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REF 1 | Tyrosyl-DNA phosphodiesterase inhibitors: Progress and potential. Bioorg Med Chem. 2016 Nov 1;24(21):5017-5027. | |||||
REF 2 | Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2. Biochem J. 2016 Jul 1;473(13):1869-79. |
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