Target Information
| Target General Information | Top | |||||
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| Target ID |
T42658
(Former ID: TTDI02456)
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| Target Name |
Herpesvirus ubiquitin-specific protease (HAUSP)
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| Synonyms |
Ubiquitin-specific-processing protease 7; Ubiquitin thioesterase 7; Ubiquitin carboxyl-terminal hydrolase 7; Herpesvirus-associated ubiquitin-specific protease; Deubiquitinating enzyme 7
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| Gene Name |
USP7
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| Target Type |
Preclinical target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Postoperative inflammation [ICD-11: 1A00-CA43] | |||||
| 2 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Together with DAXX, prevents MDM2 self-ubiquitination and enhances the E3 ligase activity of MDM2 towards p53/TP53, thereby promoting p53/TP53 ubiquitination and proteasomal degradation. Deubiquitinates p53/TP53, preventing degradation of p53/TP53, and enhances p53/TP53-dependent transcription regulation, cell growth repression and apoptosis. Deubiquitinates p53/TP53 and MDM2 and strongly stabilizes p53/TP53 even in the presence of excess MDM2, and also induces p53/TP53-dependent cell growth repression and apoptosis. Deubiquitination of FOXO4 in presence of hydrogen peroxide is not dependent on p53/TP53 and inhibits FOXO4-induced transcriptional activity. In association with DAXX, is involved in the deubiquitination and translocation of PTEN from the nucleus to the cytoplasm, both processes that are counteracted by PML. Deubiquitinates KMT2E/MLL5 preventing KMT2E/MLL5 proteasomal-mediated degradation. Involved in cell proliferation during early embryonic development. Involved in transcription-coupled nucleotide excision repair (TC-NER) in response to UV damage: recruited to DNA damage sites following interaction with KIAA1530/UVSSA and promotes deubiquitination of ERCC6, preventing UV-induced degradation of ERCC6. Involved in maintenance of DNA methylation via its interaction with UHRF1 and DNMT1: acts by mediating deubiquitination of UHRF1 and DNMT1, preventing their degradation and promoting DNA methylation by DNMT1. Deubiquitinates alkylation repair enzyme ALKBH3. OTUD4 recruits USP7 and USP9X to stabilize ALKBH3, thereby promoting the repair of alkylated DNA lesions. Acts as a chromatin regulator via its association with the Polycomb group (PcG) multiprotein PRC1-like complex; may act by deubiquitinating components of the PRC1-like complex. Able to mediate deubiquitination of histone H2B; it is however unsure whether this activity takes place in vivo. Exhibits a preference towards 'Lys-48'-linked ubiquitin chains. Increases regulatory T-cells (Treg) suppressive capacity by deubiquitinating and stabilizing the transcription factor FOXP3 which is crucial for Treg cell function. Plays a role in the maintenance of the circadian clock periodicity via deubiquitination and stabilization of the CRY1 and CRY2 proteins. Deubiquitinates REST, thereby stabilizing REST and promoting the maintenance of neural progenitor cells. Hydrolase that deubiquitinates target proteins such as FOXO4, p53/TP53, MDM2, ERCC6, DNMT1, UHRF1, PTEN, KMT2E/MLL5 and DAXX.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.19.12
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| Sequence |
MNHQQQQQQQKAGEQQLSEPEDMEMEAGDTDDPPRITQNPVINGNVALSDGHNTAEEDME
DDTSWRSEATFQFTVERFSRLSESVLSPPCFVRNLPWKIMVMPRFYPDRPHQKSVGFFLQ CNAESDSTSWSCHAQAVLKIINYRDDEKSFSRRISHLFFHKENDWGFSNFMAWSEVTDPE KGFIDDDKVTFEVFVQADAPHGVAWDSKKHTGYVGLKNQGATCYMNSLLQTLFFTNQLRK AVYMMPTEGDDSSKSVPLALQRVFYELQHSDKPVGTKKLTKSFGWETLDSFMQHDVQELC RVLLDNVENKMKGTCVEGTIPKLFRGKMVSYIQCKEVDYRSDRREDYYDIQLSIKGKKNI FESFVDYVAVEQLDGDNKYDAGEHGLQEAEKGVKFLTLPPVLHLQLMRFMYDPQTDQNIK INDRFEFPEQLPLDEFLQKTDPKDPANYILHAVLVHSGDNHGGHYVVYLNPKGDGKWCKF DDDVVSRCTKEEAIEHNYGGHDDDLSVRHCTNAYMLVYIRESKLSEVLQAVTDHDIPQQL VERLQEEKRIEAQKRKERQEAHLYMQVQIVAEDQFCGHQGNDMYDEEKVKYTVFKVLKNS SLAEFVQSLSQTMGFPQDQIRLWPMQARSNGTKRPAMLDNEADGNKTMIELSDNENPWTI FLETVDPELAASGATLPKFDKDHDVMLFLKMYDPKTRSLNYCGHIYTPISCKIRDLLPVM CDRAGFIQDTSLILYEEVKPNLTERIQDYDVSLDKALDELMDGDIIVFQKDDPENDNSEL PTAKEYFRDLYHRVDVIFCDKTIPNDPGFVVTLSNRMNYFQVAKTVAQRLNTDPMLLQFF KSQGYRDGPGNPLRHNYEGTLRDLLQFFKPRQPKKLYYQQLKMKITDFENRRSFKCIWLN SQFREEEITLYPDKHGCVRDLLEECKKAVELGEKASGKLRLLEIVSYKIIGVHQEDELLE CLSPATSRTFRIEEIPLDQVDIDKENEMLVTVAHFHKEVFGTFGIPFLLRIHQGEHFREV MKRIQSLLDIQEKEFEKFKFAIVMMGRHQYINEDEYEVNLKDFEPQPGNMSHPRPWLGLD HFNKAPKRSRYTYLEKAIKIHN Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Preclinical Drug(s) | [+] 5 Preclinical Drugs | + | ||||
| 1 | ADC-01 | Drug Info | Preclinical | Solid tumour/cancer | [2] | |
| 2 | ADC-03 | Drug Info | Preclinical | Solid tumour/cancer | [2] | |
| 3 | HBX19818 | Drug Info | Preclinical | Solid tumour/cancer | [3] | |
| 4 | P22077 | Drug Info | Preclinical | Inflammation | [4] | |
| 5 | P5091 | Drug Info | Preclinical | Solid tumour/cancer | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 7 Inhibitor drugs | + | ||||
| 1 | PMID26077642-Compound-Vif1 | Drug Info | [1] | |||
| 2 | PMID26077642-Compound-Vif2 | Drug Info | [1] | |||
| 3 | ADC-01 | Drug Info | [5] | |||
| 4 | ADC-03 | Drug Info | [5] | |||
| 5 | HBX19818 | Drug Info | [3] | |||
| 6 | P22077 | Drug Info | [4] | |||
| 7 | P5091 | Drug Info | [6] | |||
| 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: Bound form of Eupalinolide B | Ligand Info | |||||
| Structure Description | Crystal structure of USP7 in complex with its inhibitor | PDB:7XPY | ||||
| Method | X-ray diffraction | Resolution | 2.35 Å | Mutation | No | [7] |
| PDB Sequence |
GPLGSEAHLY
564 MQVQIVAEDQ574 FCGHQGNDMY584 DEEKVKYTVF594 KVLKNSSLAE604 FVQSLSQTMG 614 FPQDQIRLWP624 MQARSNGTKR634 PAMLDNEADG644 NKTMIELSDN654 ENPWTIFLET 664 VDPELAGATL676 PKFDKDHDVM686 LFLKMYDPKT696 RSLNYCGHIY706 TPISCKIRDL 716 LPVMCDRAGF726 IQDTSLILYE736 EVKPNLTERI746 QDYDVSLDKA756 LDELMDGDII 766 VFQKDDPEND776 NSELPTAKEY786 FRDLYHRVDV796 IFCDKTIPND806 PGFVVTLSNR 816 MNYFQVAKTV826 AQRLNTDPML836 LQFFKSQGYR846 DGPGNPLRHN856 YEGTLRDLLQ 866 FFKPRQPKKL876 YYQQLKMKIT886 DFENRRSFKC896 IWLNSQFREE906 EITLYPDKHG 916 CVRDLLEECK926 KAVELGEKAS936 GKLRLLEIVS946 YKIIGVHQED956 ELLECLSPAT 966 SRTFRIEEIP976 LDQVDIDKEN986 EMLVTVAHFH996 KEVFGTFGIP1006 FLLRIHQGEH 1016 FREVMKRIQS1026 LLDIQEKEFE1036 KFKFAIVMMG1046 RHQYINEDEY1056 EVNLKDFEPQ 1066 PGNMSHPRPW1076 LGLDHFNK
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| Ligand Name: 6'-amino-4'-ethyl-5'-(4-hydroxyphenyl)-N-methyl-[3,3'-bipyridine]-6-carboxamide | Ligand Info | |||||
| Structure Description | USP7 in complex with GNE6776 (6'-amino-4'-ethyl-5'-(4-hydroxyphenyl)-N-methyl-[3,3'-bipyridine]-6-carboxamide) | PDB:5UQX | ||||
| Method | X-ray diffraction | Resolution | 2.23 Å | Mutation | No | [8] |
| PDB Sequence |
KHTGYVGLKN
218 QGATCYMNSL228 LQTLFFTNQL238 RKAVYMMPTE248 GDDSSKSVPL258 ALQRVFYELQ 268 HSDKPVGTKK278 LTKSFGWETL288 DSFMQHDVQE298 LCRVLLDNVE308 NKMKGTCVEG 318 TIPKLFRGKM328 VSYIQCKEVD338 YRSDRREDYY348 DIQLSIKGKK358 NIFESFVDYV 368 AVEQLDGDNK378 YDAGEHGLQE388 AEKGVKFLTL398 PPVLHLQLMR408 FMYDPQTDQN 418 IKINDRFEFP428 EQLPLDEFLQ438 KTDPKDPANY448 ILHAVLVHSG458 DNHGGHYVVY 468 LNPKGDGKWC478 KFDDDVVSRC488 TKEEAIEHNY498 GGHDDDLSVR508 HCTNAYMLVY 518 IRESKLSEVL528 QAVTDHDIPQ538 QLVERLQEEK548 RIEAQK
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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).
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 Tissue Distribution
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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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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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| FoxO signaling pathway | hsa04068 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Degree | 18 | Degree centrality | 1.93E-03 | Betweenness centrality | 2.68E-03 |
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| Closeness centrality | 2.45E-01 | Radiality | 1.43E+01 | Clustering coefficient | 2.03E-01 |
| Neighborhood connectivity | 6.34E+01 | Topological coefficient | 9.87E-02 | 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 | ||||||
| Target Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| References | Top | |||||
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| REF 1 | Deubiquitinases (DUBs) and DUB inhibitors: a patent review.Expert Opin Ther Pat. 2015;25(10):1191-1208. | |||||
| REF 2 | Deubiquitylating enzymes and drug discovery: emerging opportunities. Nat Rev Drug Discov. 2018 Jan;17(1):57-78. | |||||
| REF 3 | Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells. Mol Cancer Ther. 2009 Aug;8(8):2286-95. | |||||
| REF 4 | P22077 inhibits LPS-induced inflammatory response by promoting K48-linked ubiquitination and degradation of TRAF6. Aging (Albany NY). 2020 Jun 9;12(11):10969-10982. | |||||
| REF 5 | Advances in Deubiquitinating Enzyme Inhibition and Applications in Cancer Therapeutics. Cancers (Basel). 2020 Jun 15;12(6):1579. | |||||
| REF 6 | USP7 inhibitor P5091 inhibits Wnt signaling and colorectal tumor growth. Biochem Pharmacol. 2017 May 1;131:29-39. | |||||
| REF 7 | Neuroinflammation inhibition by small-molecule targeting USP7 noncatalytic domain for neurodegenerative disease therapy. Sci Adv. 2022 Aug 12;8(32):eabo0789. | |||||
| REF 8 | USP7 small-molecule inhibitors interfere with ubiquitin binding. Nature. 2017 Oct 26;550(7677):534-538. | |||||
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