Target Information
| Target General Information | Top | |||||
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| Target ID |
T56051
(Former ID: TTDR01141)
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| Target Name |
Ubiquitin thioesterase L1 (UCHL1)
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| Synonyms |
Ubiquitin thiolesterase L1; Ubiquitin carboxyl-terminal hydrolase isozyme L1; Ubiquitin carboxy-terminal hydrolase L1; UCH-L1; PGP9.5; PGP 9.5; Neuron cytoplasmic protein 9.5
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| Gene Name |
UCHL1
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| Target Type |
Preclinical target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Ubiquitin-protein hydrolase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins. This enzyme is a thiol protease that recognizes and hydrolyzes a peptide bond at the C-terminal glycine of ubiquitin. Also binds to free monoubiquitin and may prevent its degradation in lysosomes. The homodimer may have ATP-independent ubiquitin ligase activity.
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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 |
MQLKPMEINPEMLNKVLSRLGVAGQWRFVDVLGLEEESLGSVPAPACALLLLFPLTAQHE
NFRKKQIEELKGQEVSPKVYFMKQTIGNSCGTIGLIHAVANNQDKLGFEDGSVLKQFLSE TEKMSPEDRAKCFEKNEAIQAAHDAVAQEGQCRVDDKVNFHFILFNNVDGHLYELDGRMP FPVNHGASSEDTLLKDAAKVCREFTEREQGEVRFSAVALCKAA Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T95A39 | |||||
| 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: Methyl 4-aminobutanoate | Ligand Info | |||||
| Structure Description | Crystal structure of the S18Y variant of ubiquitin carboxy terminal hydrolase L1 bound to ubiquitin vinylmethylester. | PDB:3IFW | ||||
| Method | X-ray diffraction | Resolution | 2.40 Å | Mutation | Yes | [4] |
| PDB Sequence |
MQLKPMEINP
10 EMLNKVLYRL20 GVAGQWRFVD30 VLGLEEESLG40 SVPAPACALL50 LLFPLTAQHE 60 NFRKKQIEEL70 KGQEVSPKVY80 FMKQTIGNSC90 GTIGLIHAVA100 NNQDKLGFED 110 GSVLKQFLSE120 TEKMSPEDRA130 KCFEKNEAIQ140 AAHDAVAQEG150 QCRVDDKVNF 160 HFILFNNVDG170 HLYELDGRMP180 FPVNHGASSE190 DTLLKDAAKV200 CREFTEREQG 210 EVRFSAVALC220 KAA
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: (3S)-1-(iminomethyl)-N-[1-[4-(pent-4-ynylcarbamoyl)phenyl]imidazol-4-yl]pyrrolidine-3-carboxamide | Ligand Info | |||||
| Structure Description | Structure of UCHL1 in complex with GK13S inhibitor | PDB:7ZM0 | ||||
| Method | X-ray diffraction | Resolution | 2.24 Å | Mutation | No | [5] |
| PDB Sequence |
PGSMQLKPME
7 INPEMLNKVL17 SRLGVAGQWR27 FVDVLGLEEE37 SLGSVPAPAC47 ALLLLFPLTA 57 QHENFRKKQI67 EELKGQEVSP77 KVYFMKQTIG87 NSCGTIGLIH97 AVANNQDKLG 107 FEDGSVLKQF117 LSETEKMSPE127 DRAKCFEKNE137 AIQAAHDAVA147 QEGQNFHFIL 164 FNNVDGHLYE174 LDGRMPFPVN184 HGASSEDTLL194 KDAAKVCREF204 TERERFSAVA 218 LCK
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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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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 | 7 | Degree centrality | 7.52E-04 | Betweenness centrality | 1.91E-04 |
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| Closeness centrality | 2.44E-01 | Radiality | 1.43E+01 | Clustering coefficient | 5.24E-01 |
| Neighborhood connectivity | 1.41E+02 | Topological coefficient | 2.30E-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 | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | TGF_beta_Receptor Signaling Pathway | |||||
| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | Parkinson disease | |||||
| PID Pathway | [+] 1 PID Pathways | + | ||||
| 1 | Alpha-synuclein signaling | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | Parkinsons Disease Pathway | |||||
| 2 | Proteasome Degradation | |||||
| References | Top | |||||
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| REF 1 | Structure-activity relationship, kinetic mechanism, and selectivity for a new class of ubiquitin C-terminal hydrolase-L1 (UCH-L1) inhibitors. Bioorg Med Chem Lett. 2007 Jul 1;17(13):3729-32. | |||||
| 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 | Ubiquitin vinyl methyl ester binding orients the misaligned active site of the ubiquitin hydrolase UCHL1 into productive conformation. Proc Natl Acad Sci U S A. 2010 May 18;107(20):9117-22. | |||||
| REF 5 | Structural basis for specific inhibition of the deubiquitinase UCHL1. Nat Commun. 2022 Oct 10;13(1):5950. | |||||
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