Target Information
| Target General Information | Top | |||||
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| Target ID |
T14875
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| Target Name |
Ubiquitin carboxyl-terminal hydrolase 14 (USP14)
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| Synonyms |
Ubiquitin-specific-processing protease 14; Ubiquitin thioesterase 14; TGT; Deubiquitinating enzyme 14
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| Gene Name |
USP14
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| Target Type |
Preclinical target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Neurodegenerative disorder [ICD-11: 8A20-8A23] | |||||
| 2 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Ensures the regeneration of ubiquitin at the proteasome. Is a reversibly associated subunit of the proteasome and a large fraction of proteasome-free protein exists within the cell. Required for the degradation of the chemokine receptor CXCR4 which is critical for CXCL12-induced cell chemotaxis. Serves also as a physiological inhibitor of endoplasmic reticulum-associated degradation (ERAD) under the non-stressed condition by inhibiting the degradation of unfolded endoplasmic reticulum proteins via interaction with ERN1. Indispensable for synaptic development and function at neuromuscular junctions (NMJs). Plays a role in the innate immune defense against viruses by stabilizing the viral DNA sensor CGAS and thus inhibiting its autophagic degradation. Proteasome-associated deubiquitinase which releases ubiquitin from the proteasome targeted ubiquitinated proteins.
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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 |
MPLYSVTVKWGKEKFEGVELNTDEPPMVFKAQLFALTGVQPARQKVMVKGGTLKDDDWGN
IKIKNGMTLLMMGSADALPEEPSAKTVFVEDMTEEQLASAMELPCGLTNLGNTCYMNATV QCIRSVPELKDALKRYAGALRASGEMASAQYITAALRDLFDSMDKTSSSIPPIILLQFLH MAFPQFAEKGEQGQYLQQDANECWIQMMRVLQQKLEAIEDDSVKETDSSSASAATPSKKK SLIDQFFGVEFETTMKCTESEEEEVTKGKENQLQLSCFINQEVKYLFTGLKLRLQEEITK QSPTLQRNALYIKSSKISRLPAYLTIQMVRFFYKEKESVNAKVLKDVKFPLMLDMYELCT PELQEKMVSFRSKFKDLEDKKVNQQPNTSDKKSSPQKEVKYEPFSFADDIGSNNCGYYDL QAVLTHQGRSSSSGHYVSWVKRKQDEWIKFDDDKVSIVTPEDILRLSGGGDWHIAYVLLY GPRRVEIMEEESEQ Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| 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: IU1 | Ligand Info | |||||
| Structure Description | USP14 catalytic domain with IU1 | PDB:6IIK | ||||
| Method | X-ray diffraction | Resolution | 1.97 Å | Mutation | No | [4] |
| PDB Sequence |
ELPCGLTNLG
111 NTCYMNATVQ121 CIRSVPELKD131 ALKRYAGALR141 ASGEMASAQY151 ITAALRDLFD 161 SMDKTSSSIP171 PIILLQFLHM181 AFPQFAEKGE191 QGQYLQQDAN201 ECWIQMMRVL 211 QQKLEAIEDK240 SLIDQFFGVE250 FETTMKCTES260 EEEEVTKGKE270 NQLQLSCFIN 280 QEVKYLFTGL290 KLRLQEEITK300 QSPTLQRNAL310 YIKSSKISRL320 PAYLTIQMVR 330 FFNAKVLKDV347 KFPLMLDMYE357 LCTPELQEKM367 VSFRSKFKDL377 YEPFSFADDI 410 GSNNCGYYDL420 QAVLTHQGRS430 SSSGHYVSWV440 KRKQDEWIKF450 DDDKVSIVTP 460 EDILRLSGGG470 DWHIAYVLLY480 GPRRV
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| Ligand Name: 1-[1-(4-chlorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-2-(piperidin-1-yl)ethan-1-one | Ligand Info | |||||
| Structure Description | USP14 catalytic domain bind to IU1-47 | PDB:6IIL | ||||
| Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | No | [4] |
| PDB Sequence |
ELPCGLTNLG
111 NTCYMNATVQ121 CIRSVPELKD131 ALKRYAGALR141 ASGEMASAQY151 ITAALRDLFD 161 SMDKTSSSIP171 PIILLQFLHM181 AFPQFAEKGE191 QGQYLQQDAN201 ECWIQMMRVL 211 QQKLEAIEDK240 SLIDQFFGVE250 FETTMKCTES260 EEEEVTKGKE270 NQLQLSCFIN 280 QEVKYLFTGL290 KLRLQEEITK300 QSPTLQRNAL310 YIKSSKISRL320 PAYLTIQMVR 330 FFNAKVLKDV347 KFPLMLDMYE357 LCTPELQEKM367 VSFRSKFKDL377 EDKKYEPFSF 406 ADDIGSNNCG416 YYDLQAVLTH426 QGRSSSSGHY436 VSWVKRKQDE446 WIKFDDDKVS 456 IVTPEDILRL466 SGGGDWHIAY476 VLLYGPRRVE486 I
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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 | 39 | Degree centrality | 4.19E-03 | Betweenness centrality | 4.48E-04 |
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| Closeness centrality | 2.21E-01 | Radiality | 1.39E+01 | Clustering coefficient | 8.45E-01 |
| Neighborhood connectivity | 5.46E+01 | Topological coefficient | 1.45E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| 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 | Emerging therapies targeting the ubiquitin proteasome system in cancer. J Clin Invest. 2014 Jan;124(1):6-12. | |||||
| REF 4 | Small molecule inhibitors reveal allosteric regulation of USP14 via steric blockade. Cell Res. 2018 Dec;28(12):1186-1194. | |||||
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