Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ8NWJD)

• DOT Name: Membrane cofactor protein (CD46)
• Synonyms: TLX; Trophoblast leukocyte common antigen; CD antigen CD46
• Gene Name: CD46
• Related Disease: Atypical hemolytic-uremic syndrome with MCP/CD46 anomaly
• UniProt ID: MCP_HUMAN
• PDB ID: 1CKL; 2O39; 3INB; 3L89; 3O8E; 5FO8; 8QK3
• Pfam ID: PF00084
• Sequence:
  MEPPGRRECPFPSWRFPGLLLAAMVLLLYSFSDACEEPPTFEAMELIGKPKPYYEIGERV
  DYKCKKGYFYIPPLATHTICDRNHTWLPVSDDACYRETCPYIRDPLNGQAVPANGTYEFG
  YQMHFICNEGYYLIGEEILYCELKGSVAIWSGKPPICEKVLCTPPPKIKNGKHTFSEVEV
  FEYLDAVTYSCDPAPGPDPFSLIGESTIYCGDNSVWSRAAPECKVVKCRFPVVENGKQIS
  GFGKKFYYKATVMFECDKGFYLDGSDTIVCDSNSTWDPPVPKCLKVLPPSSTKPPALSHS
  VSTSSTTKSPASSASGPRPTYKPPVSNYPGYPKPEEGILDSLDVWVIAVIVIAIVVGVAV
  ICVVPYRYLQRRKKKGTYLTDETHREVKFTSL
• Function: Acts as a cofactor for complement factor I, a serine protease which protects autologous cells against complement-mediated injury by cleaving C3b and C4b deposited on host tissue. May be involved in the fusion of the spermatozoa with the oocyte during fertilization. Also acts as a costimulatory factor for T-cells which induces the differentiation of CD4+ into T-regulatory 1 cells. T-regulatory 1 cells suppress immune responses by secreting interleukin-10, and therefore are thought to prevent autoimmunity; (Microbial infection) A number of viral and bacterial pathogens seem to bind MCP in order to exploit its immune regulation property and directly induce an immunosuppressive phenotype in T-cells.; (Microbial infection) Acts as a receptor for Adenovirus subgroup B2 and Ad3; (Microbial infection) Acts as a receptor for cultured Measles virus; (Microbial infection) Acts as a receptor for Herpesvirus 6/HHV-6; (Microbial infection) May act as a receptor for pathogenic bacteria Neisseria and Streptococcus pyogenes.
• Tissue Specificity: Expressed by all cells except erythrocytes.
• KEGG Pathway:
  Virion - Adenovirus (hsa03267)
  Complement and coagulation cascades (hsa04610)
  Measles (hsa05162)
• Reactome Pathway: Regulation of Complement cascade (R-HSA-977606)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atypical hemolytic-uremic syndrome with MCP/CD46 anomaly	DISJ0S64	Definitive	Semidominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Membrane cofactor protein (CD46) increases the response to substance of Paclitaxel.	[17]

16 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 Membrane cofactor protein (CD46).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Membrane cofactor protein (CD46).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Membrane cofactor protein (CD46).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Membrane cofactor protein (CD46).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Membrane cofactor protein (CD46).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Membrane cofactor protein (CD46).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Membrane cofactor protein (CD46).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Membrane cofactor protein (CD46).	[9]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Membrane cofactor protein (CD46).	[10]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Membrane cofactor protein (CD46).	[11]
Enzalutamide	DMGL19D	Approved	Enzalutamide increases the expression of Membrane cofactor protein (CD46).	[12]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline decreases the expression of Membrane cofactor protein (CD46).	[13]
ABIRATERONE	DM8V75C	Approved	ABIRATERONE increases the expression of Membrane cofactor protein (CD46).	[12]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol increases the expression of Membrane cofactor protein (CD46).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Membrane cofactor protein (CD46).	[15]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Membrane cofactor protein (CD46).	[16]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] 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.
• [9] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [10] Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells. Front Physiol. 2016 Nov 24;7:559. doi: 10.3389/fphys.2016.00559. eCollection 2016.
• [11] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [12] Targeting CD46 for both adenocarcinoma and neuroendocrine prostate cancer. JCI Insight. 2018 Sep 6;3(17):e121497. doi: 10.1172/jci.insight.121497. eCollection 2018 Sep 6.
• [13] Controlled diesel exhaust and allergen coexposure modulates microRNA and gene expression in humans: Effects on inflammatory lung markers. J Allergy Clin Immunol. 2016 Dec;138(6):1690-1700. doi: 10.1016/j.jaci.2016.02.038. Epub 2016 Apr 24.
• [14] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [15] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [16] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.
• [17] cDNA microarray analysis of isogenic paclitaxel- and doxorubicin-resistant breast tumor cell lines reveals distinct drug-specific genetic signatures of resistance. Breast Cancer Res Treat. 2006 Mar;96(1):17-39. doi: 10.1007/s10549-005-9026-6. Epub 2005 Dec 2.