Target Information
| Target General Information | Top | |||||
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| Target ID |
T17067
(Former ID: TTDI03611)
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| Target Name |
Isopeptidase T (USP5)
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| Synonyms |
Ubiquitin-specific-processing protease 5; Ubiquitin thioesterase 5; Ubiquitin carboxyl-terminal hydrolase 5; ISOT; Deubiquitinating enzyme 5
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| Gene Name |
USP5
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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 |
Involved in unanchored 'Lys-48'-linked polyubiquitin disassembly. Binds linear and 'Lys-63'-linked polyubiquitin with a lower affinity. Knock-down of USP5 causes the accumulation of p53/TP53 and an increase in p53/TP53 transcriptional activity because the unanchored polyubiquitin that accumulates is able to compete with ubiquitinated p53/TP53 but not with MDM2 for proteasomal recognition. Cleaves linear and branched multiubiquitin polymers with a marked preference for branched polymers.
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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 |
MAELSEEALLSVLPTIRVPKAGDRVHKDECAFSFDTPESEGGLYICMNTFLGFGKQYVER
HFNKTGQRVYLHLRRTRRPKEEDPATGTGDPPRKKPTRLAIGVEGGFDLSEEKFELDEDV KIVILPDYLEIARDGLGGLPDIVRDRVTSAVEALLSADSASRKQEVQAWDGEVRQVSKHA FSLKQLDNPARIPPCGWKCSKCDMRENLWLNLTDGSILCGRRYFDGSGGNNHAVEHYRET GYPLAVKLGTITPDGADVYSYDEDDMVLDPSLAEHLSHFGIDMLKMQKTDKTMTELEIDM NQRIGEWELIQESGVPLKPLFGPGYTGIRNLGNSCYLNSVVQVLFSIPDFQRKYVDKLEK IFQNAPTDPTQDFSTQVAKLGHGLLSGEYSKPVPESGDGERVPEQKEVQDGIAPRMFKAL IGKGHPEFSTNRQQDAQEFFLHLINMVERNCRSSENPNEVFRFLVEEKIKCLATEKVKYT QRVDYIMQLPVPMDAALNKEELLEYEEKKRQAEEEKMALPELVRAQVPFSSCLEAYGAPE QVDDFWSTALQAKSVAVKTTRFASFPDYLVIQIKKFTFGLDWVPKKLDVSIEMPEELDIS QLRGTGLQPGEEELPDIAPPLVTPDEPKGSLGFYGNEDEDSFCSPHFSSPTSPMLDESVI IQLVEMGFPMDACRKAVYYTGNSGAEAAMNWVMSHMDDPDFANPLILPGSSGPGSTSAAA DPPPEDCVTTIVSMGFSRDQALKALRATNNSLERAVDWIFSHIDDLDAEAAMDISEGRSA ADSISESVPVGPKVRDGPGKYQLFAFISHMGTSTMCGHYVCHIKKEGRWVIYNDQKVCAS EKPPKDLGYIYFYQRVAS Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T90XMB | |||||
| Drugs and Modes of Action | Top | |||||
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| Preclinical Drug(s) | [+] 2 Preclinical Drugs | + | ||||
| 1 | BAP-15 | Drug Info | Preclinical | Solid tumour/cancer | [2] | |
| 2 | vialinin A | Drug Info | Preclinical | Inflammation | [3] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 2 Inhibitor drugs | + | ||||
| 1 | BAP-15 | Drug Info | [4] | |||
| 2 | vialinin A | Drug Info | [1] | |||
| 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: Ethylamine | Ligand Info | |||||
| Structure Description | Covalent Ubiquitin-Usp5 Complex | PDB:3IHP | ||||
| Method | X-ray diffraction | Resolution | 2.80 Å | Mutation | No | [5] |
| PDB Sequence |
MAELSEEALL
10 SVLPTIRVPK20 AGDRVHKDEC30 AFSFDTPESE40 GGLYICMNTF50 LGFGKQYVER 60 HFNKTGQRVY70 LHLRRTDEDV120 KIVILPDYLE130 IARDGLGGLP140 DIVRDRVTSA 150 VEALLSVRQV176 SKHAFSLKQL186 DNPARIPPCG196 WKCSKCDMRE206 NLWLNLTDGS 216 ILCGRRYDGS227 GGNNHAVEHY237 RETGYPLAVK247 LGTITPDGAD257 VYSYDEDDMV 267 LDPSLAEHLS277 HFGIDMPLFG322 PGYTGIRNLG332 NSCYLNSVVQ342 VLFSIPDFQR 352 KYVDKLEKIF362 QNAPTDPTQD372 FSTQVAKLGH382 GLLSGEDGIA413 PRMFKALIGK 423 GHPEFSTNRQ433 QDAQEFFLHL443 INMVERNCRS453 SENPNEVFRF463 LVEEKIKCLA 473 TEKVKYTQRV483 DYIMQLPVPM493 DAALNKEELL503 EYEEKKRQAE513 EEKMALPELV 523 RAQVPFSSCL533 EAYGAPEQVD543 DFWSTALQAK553 SVAVKTTRFA563 SFPDYLVIQI 573 KKFTFGLDWV583 PKKLDVSIEM593 PEELDISQLR603 GTGLQPGEEE613 LPDIESVIIQ 639 LVEMGFPMDA649 CRKAVYYTGN659 SGAEAAMNWV669 MSHMDDPDFA679 NPLILPPPED 702 CVTTIVSMGF712 SRDQALKALR722 ATNNSLERAV732 DWIFSHIDDL742 DAEAAMDPKV 771 RDGPGKYQLF781 AFISHMGTST791 MCGHYVCHIK801 KEGRWVIYND811 QKVCASEKPP 821 KDLGYIYFYQ831 RVA
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| Ligand Name: Usp5-IN-1 | Ligand Info | |||||
| Structure Description | Structure of USP5 zinc-finger ubiquitin binding domain co-crystallized with (5-((4-(4-chlorophenyl)piperidin-1-yl)sulfonyl)picolinoyl)glycine | PDB:7MS7 | ||||
| Method | X-ray diffraction | Resolution | 1.45 Å | Mutation | No | [6] |
| PDB Sequence |
VRQVSKHAFS
182 LKQLDNPARI192 PPCGWKCSKC202 DMRENLWLNL212 TDGSILCGRR222 YFDGSGGNNH 232 AVEHYRETGY242 PLAVKLGTIT252 PDGADVYSYD262 EDDMVLDPSL272 AEHLSHFGID 282 MLK
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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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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 | 3 | Degree centrality | 3.22E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 2.16E-01 | Radiality | 1.38E+01 | Clustering coefficient | 1.00E+00 |
| Neighborhood connectivity | 1.52E+02 | Topological coefficient | 5.26E-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 | ||||||
| Target Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| References | Top | |||||
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| REF 1 | Vialinin A is a ubiquitin-specific peptidase inhibitor. Bioorg Med Chem Lett. 2013 Aug 1;23(15):4328-31. | |||||
| REF 2 | Emerging therapies targeting the ubiquitin proteasome system in cancer. J Clin Invest. 2014 Jan;124(1):6-12. | |||||
| REF 3 | Deubiquitylating enzymes and drug discovery: emerging opportunities. Nat Rev Drug Discov. 2018 Jan;17(1):57-78. | |||||
| REF 4 | The proteasome deubiquitinase inhibitor bAP15 downregulates TGF-/Smad signaling and induces apoptosis via UCHL5 inhibition in ovarian cancer. Oncotarget. 2019 Oct 15;10(57):5932-5948. | |||||
| REF 5 | Covalent Ubiquitin-Usp5 Complex | |||||
| REF 6 | Structure-Activity Relationship of USP5 Inhibitors. J Med Chem. 2021 Oct 28;64(20):15017-15036. | |||||
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