Target Information
| Target General Information | Top | |||||
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| Target ID |
T33492
(Former ID: TTDI02629)
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| Target Name |
Tyrosyl-DNA phosphodiesterase 1 (TDP1)
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| Synonyms |
Tyr-DNA phosphodiesterase 1
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| Gene Name |
TDP1
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| Target Type |
Patented-recorded target
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[1] | ||||
| Function |
Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase I active site tyrosine residue. Hydrolyzes 3'-phosphoglycolates on protruding 3' ends on DNA double-strand breaks due to DNA damage by radiation and free radicals. Acts on blunt-ended double-strand DNA breaks and on single-stranded DNA. Has low 3'exonuclease activity and can remove a single nucleoside from the 3'end of DNA and RNA molecules with 3'hydroxyl groups. Has no exonuclease activity towards DNA or RNA with a 3'phosphate. DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 3'-phosphodiester bond, giving rise to DNA with a free 3' phosphate.
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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 |
MSQEGDYGRWTISSSDESEEEKPKPDKPSTSSLLCARQGAANEPRYTCSEAQKAAHKRKI
SPVKFSNTDSVLPPKRQKSGSQEDLGWCLSSSDDELQPEMPQKQAEKVVIKKEKDISAPN DGTAQRTENHGAPACHRLKEEEDEYETSGEGQDIWDMLDKGNPFQFYLTRVSGVKPKYNS GALHIKDILSPLFGTLVSSAQFNYCFDVDWLVKQYPPEFRKKPILLVHGDKREAKAHLHA QAKPYENISLCQAKLDIAFGTHHTKMMLLLYEEGLRVVIHTSNLIHADWHQKTQGIWLSP LYPRIADGTHKSGESPTHFKADLISYLMAYNAPSLKEWIDVIHKHDLSETNVYLIGSTPG RFQGSQKDNWGHFRLKKLLKDHASSMPNAESWPVVGQFSSVGSLGADESKWLCSEFKESM LTLGKESKTPGKSSVPLYLIYPSVENVRTSLEGYPAGGSLPYSIQTAEKQNWLHSYFHKW SAETSGRSNAMPHIKTYMRPSPDFSKIAWFLVTSANLSKAAWGALEKNGTQLMIRSYELG VLFLPSAFGLDSFKVKQKFFAGSQEPMATFPVPYDLPPELYGSKDRPWIWNIPYVKAPDT HGNMWVPS Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T54H9V | |||||
| 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: Spermine | Ligand Info | |||||
| Structure Description | Crystal structure of human Tyrosyl-DNA Phosphodiesterase complexed with vanadate, octapeptide KLNYYDPR, and tetranucleotide AGTT. | PDB:1RFF | ||||
| Method | X-ray diffraction | Resolution | 1.70 Å | Mutation | Yes | [2] |
| PDB Sequence |
NPFQFYLTRV
171 SGVKPKYNSG181 ALHIKDILSP191 LFGTLVSSAQ201 FNYCFDVDWL211 VKQYPPEFRK 221 KPILLVHGDK231 REAKAHLHAQ241 AKPYENISLC251 QAKLDIAFGT261 HHTKMMLLLY 271 EEGLRVVIHT281 SNLIHADWHQ291 KTQGIWLSPL301 YPRIADGTHK311 SGESPTHFKA 321 NLISYLTAYN331 APSLKEWIDV341 IHKHDLSETN351 VYLIGSTPGR361 FQGSQKDNWG 371 HFRLKKLLKD381 HASSMSWPVV395 GQFSSVGSLG405 ADESKWLCSE415 FKESMLTLGV 435 PLYLIYPSVE445 NVRTSLEGYP455 AGGSLPYSIQ465 TAEKQNWLHS475 YFHKWSAETS 485 GRSNAMPHIK495 TYMRPSPDFS505 KIAWFLVTSA515 NLSKAAWGAL525 EKNGTQLMIR 535 SYELGVLFLP545 SALGLDSFKV555 KQKFATFPVP573 YDLPPELYGS583 KDRPWIWNIP 593 YVKAPDTHGN603 MWVPS
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Octopamine | Ligand Info | |||||
| Structure Description | Crystal structure of human Tyrosyl-DNA Phosphodiesterase complexed with vanadate, octopamine, and tetranucleotide AGTC | PDB:1RGT | ||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | Yes | [2] |
| PDB Sequence |
NPFQFYLTRV
171 SGVKPKYNSG181 ALHIKDILSP191 LFGTLVSSAQ201 FNYCFDVDWL211 VKQYPPEFRK 221 KPILLVHGDK231 REAKAHLHAQ241 AKPYENISLC251 QAKLDIAFGT261 HHTKMMLLLY 271 EEGLRVVIHT281 SNLIHADWHQ291 KTQGIWLSPL301 YPRIADGTHK311 SGESPTHFKA 321 NLISYLTAYN331 APSLKEWIDV341 IHKHDLSETN351 VYLIGSTPGR361 FQGSQKDNWG 371 HFRLKKLLKD381 HASSMSWPVV395 GQFSSVGSLG405 ADESKWLCSE415 FKESMLTLGV 435 PLYLIYPSVE445 NVRTSLEGYP455 AGGSLPYSIQ465 TAEKQNWLHS475 YFHKWSAETS 485 GRSNAMPHIK495 TYMRPSPDFS505 KIAWFLVTSA515 NLSKAAWGAL525 EKNGTQLMIR 535 SYELGVLFLP545 SALGLDSFKV555 KQKFTFPVPY574 DLPPELYGSK584 DRPWIWNIPY 594 VKAPDTHGNM604 WVPS
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| 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 | 9 | Degree centrality | 9.67E-04 | Betweenness centrality | 8.78E-06 |
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| Closeness centrality | 2.05E-01 | Radiality | 1.36E+01 | Clustering coefficient | 5.00E-01 |
| Neighborhood connectivity | 1.92E+01 | Topological coefficient | 2.73E-01 | 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 | Virtual Screening for the Development of Dual-Inhibitors Targeting Topoisomerase IB and Tyrosyl-DNA Phosphodiesterase 1. Curr Drug Targets. 2017;18(5):544-555. | |||||
| REF 2 | Explorations of peptide and oligonucleotide binding sites of tyrosyl-DNA phosphodiesterase using vanadate complexes. J Med Chem. 2004 Feb 12;47(4):829-37. | |||||
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