Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7Z5LNF)

• DOT Name: T-cell surface glycoprotein CD4 (CD4)
• Synonyms: T-cell surface antigen T4/Leu-3; CD antigen CD4
• Gene Name: CD4
• Related Disease: Immunodeficiency 79
• UniProt ID: CD4_HUMAN
• PDB ID: 1CDH ; 1CDI ; 1CDJ ; 1CDU ; 1CDY ; 1G9M ; 1G9N ; 1GC1 ; 1JL4 ; 1Q68 ; 1RZJ ; 1RZK ; 1WBR ; 1WIO ; 1WIP ; 1WIQ ; 2B4C ; 2JKR ; 2JKT ; 2KLU ; 2NXY ; 2NXZ ; 2NY0 ; 2NY1 ; 2NY2 ; 2NY3 ; 2NY4 ; 2NY5 ; 2NY6 ; 2QAD ; 3B71 ; 3CD4 ; 3J70 ; 3JCB ; 3JCC ; 3JWD ; 3JWO ; 3LQA ; 3O2D ; 3S4S ; 3S5L ; 3T0E ; 4H8W ; 4JM2 ; 4P9H ; 4Q6I ; 4R2G ; 4R4H ; 4RQS ; 5A7X ; 5A8H ; 5CAY ; 5THR ; 5U1F ; 5VN3 ; 6CM3 ; 6EDU ; 6L1Y ; 6MEO ; 6MET ; 6OPN ; 6OPO ; 6OPP ; 6OPQ ; 6QH6 ; 6QH7 ; 6U0L ; 6U0N ; 6URI ; 6X5B ; 6X5C ; 7T0O ; 7T0R ; 7TXD ; 8D5C ; 8FYI ; 8FYJ
• Pfam ID: PF05790 ; PF09191 ; PF00047 ; PF12104
• Sequence:
  MNRGVPFRHLLLVLQLALLPAATQGKKVVLGKKGDTVELTCTASQKKSIQFHWKNSNQIK
  ILGNQGSFLTKGPSKLNDRADSRRSLWDQGNFPLIIKNLKIEDSDTYICEVEDQKEEVQL
  LVFGLTANSDTHLLQGQSLTLTLESPPGSSPSVQCRSPRGKNIQGGKTLSVSQLELQDSG
  TWTCTVLQNQKKVEFKIDIVVLAFQKASSIVYKKEGEQVEFSFPLAFTVEKLTGSGELWW
  QAERASSSKSWITFDLKNKEVSVKRVTQDPKLQMGKKLPLHLTLPQALPQYAGSGNLTLA
  LEAKTGKLHQEVNLVVMRATQLQKNLTCEVWGPTSPKLMLSLKLENKEAKVSKREKAVWV
  LNPEAGMWQCLLSDSGQVLLESNIKVLPTWSTPVQPMALIVLGGVAGLLLFIGLGIFFCV
  RCRHRRRQAERMSQIKRLLSEKKTCQCPHRFQKTCSPI
• Function: Integral membrane glycoprotein that plays an essential role in the immune response and serves multiple functions in responses against both external and internal offenses. In T-cells, functions primarily as a coreceptor for MHC class II molecule:peptide complex. The antigens presented by class II peptides are derived from extracellular proteins while class I peptides are derived from cytosolic proteins. Interacts simultaneously with the T-cell receptor (TCR) and the MHC class II presented by antigen presenting cells (APCs). In turn, recruits the Src kinase LCK to the vicinity of the TCR-CD3 complex. LCK then initiates different intracellular signaling pathways by phosphorylating various substrates ultimately leading to lymphokine production, motility, adhesion and activation of T-helper cells. In other cells such as macrophages or NK cells, plays a role in differentiation/activation, cytokine expression and cell migration in a TCR/LCK-independent pathway. Participates in the development of T-helper cells in the thymus and triggers the differentiation of monocytes into functional mature macrophages; (Microbial infection) Primary receptor for human immunodeficiency virus-1 (HIV-1). Down-regulated by HIV-1 Vpu. Acts as a receptor for Human Herpes virus 7/HHV-7.
• Tissue Specificity: Highly expressed in T-helper cells. The presence of CD4 is a hallmark of T-helper cells which are specialized in the activation and growth of cytotoxic T-cells, regulation of B cells, or activation of phagocytes. CD4 is also present in other immune cells such as macrophages, dendritic cells or NK cells.
• KEGG Pathway:
  Viral life cycle - HIV-1 (hsa03250)
  Virion - Human immunodeficiency virus (hsa03260)
  Cytokine-cytokine receptor interaction (hsa04060)
  Cell adhesion molecules (hsa04514)
  Antigen processing and presentation (hsa04612)
  Hematopoietic cell lineage (hsa04640)
  Th1 and Th2 cell differentiation (hsa04658)
  Th17 cell differentiation (hsa04659)
  T cell receptor sig.ling pathway (hsa04660)
  Yersinia infection (hsa05135)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Human immunodeficiency virus 1 infection (hsa05170)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
  Primary immunodeficiency (hsa05340)
• Reactome Pathway:
  Nef Mediated CD4 Down-regulation (R-HSA-167590)
  Binding and entry of HIV virion (R-HSA-173107)
  Vpu mediated degradation of CD4 (R-HSA-180534)
  Downstream TCR signaling (R-HSA-202424)
  Phosphorylation of CD3 and TCR zeta chains (R-HSA-202427)
  Translocation of ZAP-70 to Immunological synapse (R-HSA-202430)
  Generation of second messenger molecules (R-HSA-202433)
  PD-1 signaling (R-HSA-389948)
  Other interleukin signaling (R-HSA-449836)
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  Alpha-defensins (R-HSA-1462054)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Immunodeficiency 79	DISIYKAE	Limited	Unknown	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of T-cell surface glycoprotein CD4 (CD4).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of T-cell surface glycoprotein CD4 (CD4).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of T-cell surface glycoprotein CD4 (CD4).	[3]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of T-cell surface glycoprotein CD4 (CD4).	[4]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of T-cell surface glycoprotein CD4 (CD4).	[5]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of T-cell surface glycoprotein CD4 (CD4).	[6]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of T-cell surface glycoprotein CD4 (CD4).	[7]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of T-cell surface glycoprotein CD4 (CD4).	[8]
Rimexolone	DMTAREC	Approved	Rimexolone decreases the expression of T-cell surface glycoprotein CD4 (CD4).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of T-cell surface glycoprotein CD4 (CD4).	[10]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of T-cell surface glycoprotein CD4 (CD4).	[6]

References

• [1] Complete Multilineage CD4 Expression Defect Associated With Warts Due to an Inherited Homozygous CD4 Gene Mutation. Front Immunol. 2019 Nov 8;10:2502. doi: 10.3389/fimmu.2019.02502. eCollection 2019.
• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] 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.
• [4] Reduction of synovial sublining layer inflammation and proinflammatory cytokine expression in psoriatic arthritis treated with methotrexate. Arthritis Rheum. 2004 Oct;50(10):3286-95. doi: 10.1002/art.20518.
• [5] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [6] Chemotaxis of human CD4+ eosinophils. Int Arch Allergy Immunol. 2001;125 Suppl 1:19-21. doi: 10.1159/000053847.
• [7] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.
• [8] Rimexolone inhibits proliferation, cytokine expression and signal transduction of human CD4+ T-cells. Immunol Lett. 2010 Jun 15;131(1):24-32. doi: 10.1016/j.imlet.2010.03.009. Epub 2010 Apr 2.
• [9] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [10] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.