Target Information
| Target General Information | Top | |||||
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| Target ID |
T66935
(Former ID: TTDR00894)
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| Target Name |
Poly [ADP-ribose] glycohydrolase (PARG)
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| Synonyms |
Poly(ADP-ribose) glycohydrolase
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| Gene Name |
PARG
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| Target Type |
Literature-reported target
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[1] | ||||
| Function |
Poly(ADP-ribose) glycohydrolase that degrades poly(ADP-ribose) by hydrolyzing the ribose-ribose bonds present in poly(ADP-ribose). PARG acts both as an endo- and exoglycosidase, releasing poly(ADP-ribose) of different length as well as ADP-ribose monomers. It is however unable to cleave the ester bond between the terminal ADP-ribose and ADP-ribosylated residues, leaving proteins that are mono-ADP-ribosylated. Poly(ADP-ribose) is synthesized after DNA damage is only present transiently and is rapidly degraded by PARG. Required to prevent detrimental accumulation of poly(ADP-ribose) upon prolonged replicative stress, while it is not required for recovery from transient replicative stress. Required for retinoid acid-dependent gene transactivation, probably by removing poly(ADP-ribose) from histone demethylase KDM4D, allowing chromatin derepression at RAR-dependent gene promoters. Involved in the synthesis of ATP in the nucleus, together with PARP1, NMNAT1 and NUDT5. Nuclear ATP generation is required for extensive chromatin remodeling events that are energy-consuming.
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| BioChemical Class |
Glycosylase
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| UniProt ID | ||||||
| EC Number |
EC 3.2.1.143
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| Sequence |
MNAGPGCEPCTKRPRWGAATTSPAASDARSFPSRQRRVLDPKDAHVQFRVPPSSPACVPG
RAGQHRGSATSLVFKQKTITSWMDTKGIKTAESESLDSKENNNTRIESMMSSVQKDNFYQ HNVEKLENVSQLSLDKSPTEKSTQYLNQHQTAAMCKWQNEGKHTEQLLESEPQTVTLVPE QFSNANIDRSPQNDDHSDTDSEENRDNQQFLTTVKLANAKQTTEDEQAREAKSHQKCSKS CDPGEDCASCQQDEIDVVPESPLSDVGSEDVGTGPKNDNKLTRQESCLGNSPPFEKESEP ESPMDVDNSKNSCQDSEADEETSPGFDEQEDGSSSQTANKPSRFQARDADIEFRKRYSTK GGEVRLHFQFEGGESRTGMNDLNAKLPGNISSLNVECRNSKQHGKKDSKITDHFMRLPKA EDRRKEQWETKHQRTERKIPKYVPPHLSPDKKWLGTPIEEMRRMPRCGIRLPLLRPSANH TVTIRVDLLRAGEVPKPFPTHYKDLWDNKHVKMPCSEQNLYPVEDENGERTAGSRWELIQ TALLNKFTRPQNLKDAILKYNVAYSKKWDFTALIDFWDKVLEEAEAQHLYQSILPDMVKI ALCLPNICTQPIPLLKQKMNHSITMSQEQIASLLANAFFCTFPRRNAKMKSEYSSYPDIN FNRLFEGRSSRKPEKLKTLFCYFRRVTEKKPTGLVTFTRQSLEDFPEWERCEKPLTRLHV TYEGTIEENGQGMLQVDFANRFVGGGVTSAGLVQEEIRFLINPELIISRLFTEVLDHNEC LIITGTEQYSEYTGYAETYRWSRSHEDGSERDDWQRRCTEIVAIDALHFRRYLDQFVPEK MRRELNKAYCGFLRPGVSSENLSAVATGNWGCGAFGGDARLKALIQILAAAAAERDVVYF TFGDSELMRDIYSMHIFLTERKLTVGDVYKLLLRYYNEECRNCSTPGPDIKLYPFIYHAV ESCAETADHSGQRTGT Click to Show/Hide
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| HIT2.0 ID | T20KA8 | |||||
| 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: S,S-(2-Hydroxyethyl)Thiocysteine | Ligand Info | |||||
| Structure Description | Structure of human PARG complexed with PARG-061 | PDB:7KG8 | ||||
| Method | X-ray diffraction | Resolution | 1.43 Å | Mutation | Yes | [3] |
| PDB Sequence |
KKWLGTPIEE
460 MRRMPRCGIR470 LPLLRPSANH480 TVTIRVDLLR490 AGEVPKPFPT500 HYKDLWDNKH 510 VKMPCSEQNL520 YAGSRWELIQ540 TALLNKFTRP550 QNLKDAILKY560 NVAYSKKWDF 570 TALIDFWDKV580 LEEAEAQHLY590 QSILPDMVKI600 ALLPNICTQP611 IPLLAAAMNH 621 SITMSQEQIA631 SLLANAFFCT641 FPRRNAKMKS651 EYSSYPDINF661 NRLFEGRSSR 671 KPEKLKTLFC681 YFRRVTAAAP691 TGLVTFTRQS701 LEDFPEWERE712 KPLTRLHVTY 722 EGTIEENGQG732 MLQVDFANRF742 VGGGVTSAGL752 VQEEIRFLIN762 PELIISRLFT 772 EVLDHNECLI782 ITGTEQYSEY792 TGYAETYRWS802 RSHEDGSERD812 DWQRRCTEIV 822 AIDALHFRRY832 LDQFVPEKMR842 RELNKAYCGF852 LRPGVSSENL862 SAVATGNWGC 872 GAFGGDARLK882 ALIQILAAAA892 AERDVVYFTF902 GDSELMRDIY912 SMHIFLTERK 922 LTVGDVYKLL932 LRYYNEECRN942 CTPGPDIKLY953 PFIYHAVES
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TRP536
4.417
VAL598
4.910
LYS599
3.098
ILE600
3.335
ALA601
3.161
LEU602
1.331
LEU604
1.328
PRO605
2.694
ASN606
2.172
ILE607
2.594
CYS608
4.391
SER632
4.164
PRO706
2.165
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Cysteine Sulfenic Acid | Ligand Info | |||||
| Structure Description | POLYADPRIBOSYL GLYCOHYDROLASE IN COMPLEX WITH PDD00013907 | PDB:6HMM | ||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | Yes | [4] |
| PDB Sequence |
DKKWLGTPIE
459 EMRRMPRCGI469 RLPLLRPSAN479 HTVTIRVDLL489 RAGEVPKPFP499 THYKDLWDNK 509 HVKMPCSEQN519 LYPVTAGSRW536 ELIQTALLNK546 FTRPQNLKDA556 ILKYNVAYSK 566 KWDFTALIDF576 WDKVLEEAEA586 QHLYQSILPD596 MVKIALCLPN606 ICTQPIPLLA 616 AAMNHSITMS626 QEQIASLLAN636 AFFCTFPRRN646 AKMKSEYSSY656 PDINFNRLFE 666 GRSSRKPEKL676 KTLFCYFRRV686 TAAAPTGLVT696 FTRQSLEDFP706 EWEREKPLTR 717 LHVTYEGTIE727 ENGQGMLQVD737 FANRFVGGGV747 TSAGLVQEEI757 RFLINPELII 767 SRLFTEVLDH777 NECLIITGTE787 QYSEYTGYAE797 TYRWSRSHED807 GSERDDWQRR 817 CTEIVAIDAL827 HFRRYLDQFV837 PEKMRRELNK847 AYCGFLRPGV857 SSENLSAVAT 867 GNWGCGAFGG877 DARLKALIQI887 LAAAAAERDV897 VYFTFGDSEL907 MRDIYSMHIF 917 LTERKLTVGD927 VYKLLLRYYN937 EECRNSTPGP948 DIKLYPFIYH958 AVESC |
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PRO706
4.656
GLU707
3.394
TRP708
3.088
GLU709
3.599
ARG710
1.349
GLU712
1.349
LYS713
3.410
LEU833
3.811
ALA892
4.633
THR924
3.424
VAL925
3.606
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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 | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 2.57E-05 |
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| Closeness centrality | 1.93E-01 | Radiality | 1.33E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 1.35E+01 | Topological coefficient | 5.21E-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 | Post-treatment with a novel PARG inhibitor reduces infarct in cerebral ischemia in the rat. Brain Res. 2003 Jul 18;978(1-2):99-103. | |||||
| REF 2 | Treatment with a novel poly(ADP-ribose) glycohydrolase inhibitor reduces development of septic shock-like syndrome induced by zymosan in mice. Crit Care Med. 2004 Jun;32(6):1365-74. | |||||
| REF 3 | Targeting SARS-CoV-2 Nsp3 macrodomain structure with insights from human poly(ADP-ribose) glycohydrolase (PARG) structures with inhibitors. Prog Biophys Mol Biol. 2021 Aug;163:171-186. | |||||
| REF 4 | Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792. | |||||
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