Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ5PR39)

• DOT Name: E3 ISG15--protein ligase HERC5 (HERC5)
• Synonyms: EC 2.3.2.-; Cyclin-E-binding protein 1; HECT domain and RCC1-like domain-containing protein 5
• Gene Name: HERC5
• Related Disease:
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Advanced cancer
  Dermatomyositis
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Influenza
  Leukemia
  Lung cancer
  Lung carcinoma
  Non-small-cell lung cancer
  Seminoma
  Alcohol dependence
  Keratitis
  Neoplasm
  Endometriosis
  Hepatitis C virus infection
• UniProt ID: HERC5_HUMAN
• EC Number: 2.3.2.-
• Pfam ID: PF00632 ; PF00415
• Sequence:
  MERRSRRKSRRNGRSTAGKAAATQPAKSPGAQLWLFPSAAGLHRALLRRVEVTRQLCCSP
  GRLAVLERGGAGVQVHQLLAGSGGARTPKCIKLGKNMKIHSVDQGAEHMLILSSDGKPFE
  YDNYSMKHLRFESILQEKKIIQITCGDYHSLALSKGGELFAWGQNLHGQLGVGRKFPSTT
  TPQIVEHLAGVPLAQISAGEAHSMALSMSGNIYSWGKNECGQLGLGHTESKDDPSLIEGL
  DNQKVEFVACGGSHSALLTQDGLLFTFGAGKHGQLGHNSTQNELRPCLVAELVGYRVTQI
  ACGRWHTLAYVSDLGKVFSFGSGKDGQLGNGGTRDQLMPLPVKVSSSEELKLESHTSEKE
  LIMIAGGNQSILLWIKKENSYVNLKRTIPTLNEGTVKRWIADVETKRWQSTKREIQEIFS
  SPACLTGSFLRKRRTTEMMPVYLDLNKARNIFKELTQKDWITNMITTCLKDNLLKRLPFH
  SPPQEALEIFFLLPECPMMHISNNWESLVVPFAKVVCKMSDQSSLVLEEYWATLQESTFS
  KLVQMFKTAVICQLDYWDESAEENGNVQALLEMLKKLHRVNQVKCQLPESIFQVDELLHR
  LNFFVEVCRRYLWKMTVDASENVQCCVIFSHFPFIFNNLSKIKLLHTDTLLKIESKKHKA
  YLRSAAIEEERESEFALRPTFDLTVRRNHLIEDVLNQLSQFENEDLRKELWVSFSGEIGY
  DLGGVKKEFFYCLFAEMIQPEYGMFMYPEGASCMWFPVKPKFEKKRYFFFGVLCGLSLFN
  CNVANLPFPLALFKKLLDQMPSLEDLKELSPDLGKNLQTLLDDEGDNFEEVFYIHFNVHW
  DRNDTNLIPNGSSITVNQTNKRDYVSKYINYIFNDSVKAVYEEFRRGFYKMCDEDIIKLF
  HPEELKDVIVGNTDYDWKTFEKNARYEPGYNSSHPTIVMFWKAFHKLTLEEKKKFLVFLT
  GTDRLQMKDLNNMKITFCCPESWNERDPIRALTCFSVLFLPKYSTMETVEEALQEAINNN
  RGFG
• Function: Major E3 ligase for ISG15 conjugation. Acts as a positive regulator of innate antiviral response in cells induced by interferon. Functions as part of the ISGylation machinery that recognizes target proteins in a broad and relatively non-specific manner. Catalyzes ISGylation of IRF3 which results in sustained activation, it attenuates IRF3-PIN1 interaction, which antagonizes IRF3 ubiquitination and degradation, and boosts the antiviral response. Mediates ISGylation of the phosphatase PTEN leading to its degradation, thus alleviating its suppression of the PI3K-AKT signaling pathway and promoting the production of cytokines that facilitate bacterial clearance. Interferes with the function of key viral structural proteins such as ebolavirus structural protein VP40 or HIV-1 protein GAG. Catalyzes ISGylation of influenza A viral NS1 which attenuates virulence; ISGylated NS1 fails to form homodimers and thus to interact with its RNA targets. Catalyzes ISGylation of papillomavirus type 16 L1 protein which results in dominant-negative effect on virus infectivity. Physically associated with polyribosomes, broadly modifies newly synthesized proteins in a cotranslational manner. In an interferon-stimulated cell, newly translated viral proteins are primary targets of ISG15. Promotes parkin/PRKN ubiquitin E3 ligase activity by suppressing the intramolecular interaction that maintains its autoinhibited conformation ; (Microbial infection) Functions as an E3 ligase for ISGylation of hepatitis B virus protein X leading to enhanced viral replication due to increased interferon resistance.
• Tissue Specificity: Expressed in testis and to a lesser degree in brain, ovary and placenta. Found in most tissues at low levels.
• Reactome Pathway:
  DDX58/IFIH1-mediated induction of interferon-alpha/beta (R-HSA-168928)
  Negative regulators of DDX58/IFIH1 signaling (R-HSA-936440)
  Antigen processing (R-HSA-983168)
  PKR-mediated signaling (R-HSA-9833482)
  ISG15 antiviral mechanism (R-HSA-1169408)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Dermatomyositis	DIS50C5O	Strong	Altered Expression	[3]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[4]
Glioma	DIS5RPEH	Strong	Altered Expression	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Influenza	DIS3PNU3	Strong	Biomarker	[6]
Leukemia	DISNAKFL	Strong	Biomarker	[7]
Lung cancer	DISCM4YA	Strong	Biomarker	[8]
Lung carcinoma	DISTR26C	Strong	Biomarker	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Posttranslational Modification	[8]
Seminoma	DIS3J8LJ	Strong	Biomarker	[9]
Alcohol dependence	DIS4ZSCO	moderate	Biomarker	[10]
Keratitis	DISMFOEI	moderate	Altered Expression	[11]
Neoplasm	DISZKGEW	moderate	Biomarker	[12]
Endometriosis	DISX1AG8	Disputed	Biomarker	[13]
Hepatitis C virus infection	DISQ0M8R	Limited	Biomarker	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[20]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[21]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[22]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[23]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[24]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[25]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[13]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[27]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[28]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[29]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[29]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[30]
Bicalutamide	DMZMSPF	Approved	Bicalutamide increases the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[31]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[29]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone decreases the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[29]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[32]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[27]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[33]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[35]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[36]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[37]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of E3 ISG15--protein ligase HERC5 (HERC5).	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of E3 ISG15--protein ligase HERC5 (HERC5).	[34]

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