Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQLBWJE)

• DOT Name: COP9 signalosome complex subunit 5 (COPS5)
• Synonyms: SGN5; Signalosome subunit 5; EC 3.4.-.-; Jun activation domain-binding protein 1
• Gene Name: COPS5
• UniProt ID: CSN5_HUMAN
• PDB ID: 4D10; 4D18; 4F7O; 4WSN; 5JOG; 5JOH; 5M5Q; 6R6H; 6R7F; 6R7H; 6R7I; 8H38; 8H3A; 8H3F
• EC Number: 3.4.-.-
• Pfam ID: PF18323 ; PF01398
• Sequence:
  MAASGSGMAQKTWELANNMQEAQSIDEIYKYDKKQQQEILAAKPWTKDHHYFKYCKISAL
  ALLKMVMHARSGGNLEVMGLMLGKVDGETMIIMDSFALPVEGTETRVNAQAAAYEYMAAY
  IENAKQVGRLENAIGWYHSHPGYGCWLSGIDVSTQMLNQQFQEPFVAVVIDPTRTISAGK
  VNLGAFRTYPKGYKPPDEGPSEYQTIPLNKIEDFGVHCKQYYALEVSYFKSSLDRKLLEL
  LWNKYWVNTLSSSSLLTNADYTTGQVFDLSEKLEQSEAQLGRGSFMLGLETHDRKSEDKL
  AKATRDSCKTTIEAIHGLMSQVIKDKLFNQINIS
• Function: Probable protease subunit of the COP9 signalosome complex (CSN), a complex involved in various cellular and developmental processes. 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.
• Reactome Pathway:
  Formation of TC-NER Pre-Incision Complex (R-HSA-6781823)
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  Neddylation (R-HSA-8951664)
  DNA Damage Recognition in GG-NER (R-HSA-5696394)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	COP9 signalosome complex subunit 5 (COPS5) increases the response to substance of Cisplatin.	[8]

6 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of COP9 signalosome complex subunit 5 (COPS5).	[1]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of COP9 signalosome complex subunit 5 (COPS5).	[2]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of COP9 signalosome complex subunit 5 (COPS5).	[3]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of COP9 signalosome complex subunit 5 (COPS5).	[4]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of COP9 signalosome complex subunit 5 (COPS5).	[6]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of COP9 signalosome complex subunit 5 (COPS5).	[7]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of COP9 signalosome complex subunit 5 (COPS5).	[5]

References

• [1] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [2] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [3] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [4] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [5] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [6] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [7] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [8] Genome-wide local ancestry approach identifies genes and variants associated with chemotherapeutic susceptibility in African Americans. PLoS One. 2011;6(7):e21920. doi: 10.1371/journal.pone.0021920. Epub 2011 Jul 6.