Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMZH7EJ)

• DOT Name: Tripartite motif-containing protein 5 (TRIM5)
• Synonyms: EC 2.3.2.27; RING finger protein 88; RING-type E3 ubiquitin transferase TRIM5
• Gene Name: TRIM5
• Related Disease:
  Malaria
  Familial Mediterranean fever
  Hepatitis B virus infection
  HIV infectious disease
  Immunodeficiency
  leukaemia
  Leukemia
  Measles
  Peripheral arterial disease
  Pharynx neoplasm
  Schizophrenia
  Autoimmune disease
  Coronary heart disease
• UniProt ID: TRIM5_HUMAN
• PDB ID: 2ECV; 2YRG
• EC Number: 2.3.2.27
• Pfam ID: PF00622 ; PF00643 ; PF13445
• Sequence:
  MASGILVNVKEEVTCPICLELLTQPLSLDCGHSFCQACLTANHKKSMLDKGESSCPVCRI
  SYQPENIRPNRHVANIVEKLREVKLSPEGQKVDHCARHGEKLLLFCQEDGKVICWLCERS
  QEHRGHHTFLTEEVAREYQVKLQAALEMLRQKQQEAEELEADIREEKASWKTQIQYDKTN
  VLADFEQLRDILDWEESNELQNLEKEEEDILKSLTNSETEMVQQTQSLRELISDLEHRLQ
  GSVMELLQGVDGVIKRTENVTLKKPETFPKNQRRVFRAPDLKGMLEVFRELTDVRRYWVD
  VTVAPNNISCAVISEDKRQVSSPKPQIIYGARGTRYQTFVNFNYCTGILGSQSITSGKHY
  WEVDVSKKTAWILGVCAGFQPDAMCNIEKNENYQPKYGYWVIGLEEGVKCSAFQDSSFHT
  PSVPFIVPLSVIICPDRVGVFLDYEACTVSFFNITNHGFLIYKFSHCSFSQPVFPYLNPR
  KCGVPMTLCSPSS
• Function: Capsid-specific restriction factor that prevents infection from non-host-adapted retroviruses. Blocks viral replication early in the life cycle, after viral entry but before reverse transcription. In addition to acting as a capsid-specific restriction factor, also acts as a pattern recognition receptor that activates innate immune signaling in response to the retroviral capsid lattice. Binding to the viral capsid triggers its E3 ubiquitin ligase activity, and in concert with the heterodimeric ubiquitin conjugating enzyme complex UBE2V1-UBE2N (also known as UBC13-UEV1A complex) generates 'Lys-63'-linked polyubiquitin chains, which in turn are catalysts in the autophosphorylation of the MAP3K7/TAK1 complex (includes TAK1, TAB2, and TAB3). Activation of the MAP3K7/TAK1 complex by autophosphorylation results in the induction and expression of NF-kappa-B and MAPK-responsive inflammatory genes, thereby leading to an innate immune response in the infected cell. Restricts infection by N-tropic murine leukemia virus (N-MLV), equine infectious anemia virus (EIAV), simian immunodeficiency virus of macaques (SIVmac), feline immunodeficiency virus (FIV), and bovine immunodeficiency virus (BIV). Plays a role in regulating autophagy through activation of autophagy regulator BECN1 by causing its dissociation from its inhibitors BCL2 and TAB2. Also plays a role in autophagy by acting as a selective autophagy receptor which recognizes and targets HIV-1 capsid protein p24 for autophagic destruction.
• KEGG Pathway:
  Viral life cycle - HIV-1 (hsa03250)
  Human immunodeficiency virus 1 infection (hsa05170)
• Reactome Pathway: Interferon gamma signaling (R-HSA-877300)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Malaria	DISQ9Y50	Definitive	Biomarker	[1]
Familial Mediterranean fever	DISVP5WP	Strong	Biomarker	[2]
Hepatitis B virus infection	DISLQ2XY	Strong	Genetic Variation	[3]
HIV infectious disease	DISO97HC	Strong	Biomarker	[4]
Immunodeficiency	DIS093I0	Strong	Genetic Variation	[5]
leukaemia	DISS7D1V	Strong	Biomarker	[2]
Leukemia	DISNAKFL	Strong	Biomarker	[2]
Measles	DISXSUID	Strong	Genetic Variation	[6]
Peripheral arterial disease	DIS78WFB	Strong	Genetic Variation	[7]
Pharynx neoplasm	DISQCA3F	Strong	Genetic Variation	[8]
Schizophrenia	DISSRV2N	Strong	Biomarker	[9]
Autoimmune disease	DISORMTM	moderate	Biomarker	[10]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Tripartite motif-containing protein 5 (TRIM5).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Tripartite motif-containing protein 5 (TRIM5).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tripartite motif-containing protein 5 (TRIM5).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tripartite motif-containing protein 5 (TRIM5).	[15]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Tripartite motif-containing protein 5 (TRIM5).	[16]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Tripartite motif-containing protein 5 (TRIM5).	[17]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Tripartite motif-containing protein 5 (TRIM5).	[18]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Tripartite motif-containing protein 5 (TRIM5).	[19]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Tripartite motif-containing protein 5 (TRIM5).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Tripartite motif-containing protein 5 (TRIM5).	[21]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Tripartite motif-containing protein 5 (TRIM5).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Tripartite motif-containing protein 5 (TRIM5).	[22]

References

• [1] Genetic polymorphisms associated with anti-malarial antibody levels in a low and unstable malaria transmission area in southern Sri Lanka.Malar J. 2012 Aug 20;11:281. doi: 10.1186/1475-2875-11-281.
• [2] Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function.Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6200-5. doi: 10.1073/pnas.0609174104. Epub 2007 Mar 30.
• [3] Relationship of TRIM5 and TRIM22 polymorphisms with liver disease and HCV clearance after antiviral therapy in HIV/HCV coinfected patients.J Transl Med. 2016 Sep 2;14(1):257. doi: 10.1186/s12967-016-1005-7.
• [4] Genetic determinants of HIV-1 infection and progression to AIDS: susceptibility to HIV infection.Tissue Antigens. 2009 Apr;73(4):289-301. doi: 10.1111/j.1399-0039.2009.01220.x.
• [5] Diversity of TRIM5 and TRIMCyp sequences in cynomolgus macaques from different geographical origins.Immunogenetics. 2012 Apr;64(4):267-78. doi: 10.1007/s00251-011-0585-x. Epub 2011 Nov 29.
• [6] Associations between polymorphisms in the antiviral TRIM genes and measles vaccine immunity.Hum Immunol. 2013 Jun;74(6):768-74. doi: 10.1016/j.humimm.2013.01.031. Epub 2013 Feb 13.
• [7] Genetic Variants in the Bone Morphogenic Protein Gene Family Modify the Association between Residential Exposure to Traffic and Peripheral Arterial Disease.PLoS One. 2016 Apr 15;11(4):e0152670. doi: 10.1371/journal.pone.0152670. eCollection 2016.
• [8] Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer.Nat Genet. 2016 Dec;48(12):1544-1550. doi: 10.1038/ng.3685. Epub 2016 Oct 17.
• [9] A pilot study on commonality and specificity of copy number variants in schizophrenia and bipolar disorder.Transl Psychiatry. 2016 May 31;6(5):e824. doi: 10.1038/tp.2016.96.
• [10] Restriction of HIV-1 and other retroviruses by TRIM5.Nat Rev Microbiol. 2019 Sep;17(9):546-556. doi: 10.1038/s41579-019-0225-2. Epub 2019 Jul 16.
• [11] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [14] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [15] 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.
• [16] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [17] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [18] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [19] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [20] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [21] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [22] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [23] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.