Target Information
| Target General Information | Top | |||||
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| Target ID |
T84791
(Former ID: TTDR00901)
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| Target Name |
JUN activation domain binding protein (COPS5)
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| Synonyms |
Signalosome subunit 5; SGN5; Jun activation domain-binding protein 1; JAB1; CSN5; COP9 signalosome complex subunit 5
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| Gene Name |
COPS5
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| Target Type |
Literature-reported target
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| Function |
The CSN complex is an essential regulator of the ubiquitin (Ubl) conjugation pathway by mediating the deneddylation of the cullin subunits of the SCF-type E3 ligase complexes, leading to decrease the Ubl ligase activity of SCF-type complexes such as SCF, CSA or DDB2. The complex is also involved in phosphorylation of p53/TP53, c-jun/JUN, IkappaBalpha/NFKBIA, ITPK1 and IRF8, possibly via its association with CK2 and PKD kinases. CSN-dependent phosphorylation of TP53 and JUN promotes and protects degradation by the Ubl system, respectively. In the complex, it probably acts as the catalytic center that mediates the cleavage of Nedd8 from cullins. It however has no metalloprotease activity by itself and requires the other subunits of the CSN complex. Interacts directly with a large number of proteins that are regulated by the CSN complex, confirming a key role in the complex. Promotes the proteasomal degradation of BRSK2. Probable protease subunit of the COP9 signalosome complex (CSN), a complex involved in various cellular and developmental processes.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.-.-
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| Sequence |
MAASGSGMAQKTWELANNMQEAQSIDEIYKYDKKQQQEILAAKPWTKDHHYFKYCKISAL
ALLKMVMHARSGGNLEVMGLMLGKVDGETMIIMDSFALPVEGTETRVNAQAAAYEYMAAY IENAKQVGRLENAIGWYHSHPGYGCWLSGIDVSTQMLNQQFQEPFVAVVIDPTRTISAGK VNLGAFRTYPKGYKPPDEGPSEYQTIPLNKIEDFGVHCKQYYALEVSYFKSSLDRKLLEL LWNKYWVNTLSSSSLLTNADYTTGQVFDLSEKLEQSEAQLGRGSFMLGLETHDRKSEDKL AKATRDSCKTTIEAIHGLMSQVIKDKLFNQINIS 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: 2'-Chloro-6-[(5s,6s)-6-Hydroxy-6,7,8,9-Tetrahydro-5h-Imidazo[1,5-A]azepin-5-Yl][1,1'-Biphenyl]-3-Carbonitrile | Ligand Info | |||||
| Structure Description | CRYSTAL STRUCTURE OF CSN5(2-257) IN COMPLEX WITH CNS5i-1b | PDB:5JOH | ||||
| Method | X-ray diffraction | Resolution | 1.99 Å | Mutation | No | [2] |
| PDB Sequence |
SGSGMAQKTW
13 ELANNMQEAQ23 SIDEIYKYDK33 KQQQEILAAK43 PWTKDHHYFK53 YCKISALALL 63 KMVMHARSGG73 NLEVMGLMLG83 KVDGETMIIM93 DSFALPVNAQ110 AAAYEYMAAY 120 IENAKQVGRL130 ENAIGWYHSH140 PGYGCWLSGI150 DVSTQMLNQQ160 FQEPFVAVVI 170 DPTRKVNLGA185 FRTYPKGYKP195 PDEGPSEYQT205 IPLNKIEDFG215 VHCKQYYALE 225 VSYFKSSLDR235 K
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| Ligand Name: 1-[(3~{r})-3-(1~{h}-Benzimidazol-2-Yl)morpholin-4-Yl]-3-[2-(4-Methyl-2-Phenyl-Phenyl)-1~{h}-Pyrrolo[2,3-B]pyridin-3-Yl]propan-1-One | Ligand Info | |||||
| Structure Description | COPS5(2-257) IN COMPLEX WITH A AZAINDOLE (COMPOUND 4) | PDB:5M5Q | ||||
| Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | No | [3] |
| PDB Sequence |
SGSGMAQKTW
13 ELANNMQEAQ23 SIDEIYKYDK33 KQQQEILAAK43 PWTKDHHYFK53 YCKISALALL 63 KMVMHARSGG73 NLEVMGLMLG83 KVDGETMIIM93 DSFALPAQAA112 AYEYMAAYIE 122 NAKQVGRLEN132 AIGWYHSHPG142 YGCWLSGIDV152 STQMLNQQFQ162 EPFVAVVIDP 172 TRKVNLGAFR187 TYPKGYKPPD197 EGPSEYQTIP207 LNKIEDFGVH217 CKQYYALEVS 227 YFKSSLDRK
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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 | 35 | Degree centrality | 3.76E-03 | Betweenness centrality | 2.88E-03 |
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| Closeness centrality | 2.47E-01 | Radiality | 1.43E+01 | Clustering coefficient | 2.74E-01 |
| Neighborhood connectivity | 3.67E+01 | Topological coefficient | 5.34E-02 | Eccentricity | 11 |
| 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 | Jun activation domain-binding protein 1 expression in breast cancer inversely correlates with the cell cycle inhibitor p27(Kip1). Cancer Res. 2003 Jun 1;63(11):2977-81. | |||||
| REF 2 | Targeted inhibition of the COP9 signalosome for treatment of cancer. Nat Commun. 2016 Oct 24;7:13166. | |||||
| REF 3 | Azaindoles as Zinc-Binding Small-Molecule Inhibitors of the JAMM Protease CSN5. Angew Chem Int Ed Engl. 2017 Jan 24;56(5):1294-1297. | |||||
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