Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXN18OA)

• DOT Name: Killer cell immunoglobulin-like receptor 2DL4 (KIR2DL4)
• Synonyms: CD158 antigen-like family member D; G9P; Killer cell inhibitory receptor 103AS; KIR-103AS; MHC class I NK cell receptor KIR103AS; CD antigen CD158d
• Gene Name: KIR2DL4
• Related Disease:
  Endometriosis
  Lupus
  Non-small-cell lung cancer
  Systemic lupus erythematosus
  Adult lymphoma
  Langerhans cell histiocytosis
  Langerhans cell histiocytosis specific to childhood
  Lymphoma
  Mastocytosis
  Pediatric lymphoma
  Asthma
• UniProt ID: KI2L4_HUMAN
• PDB ID: 3WYR
• Pfam ID: PF00047
• Sequence:
  MSMSPTVIILACLGFFLDQSVWAHVGGQDKPFCSAWPSAVVPQGGHVTLRCHYRRGFNIF
  TLYKKDGVPVPELYNRIFWNSFLISPVTPAHAGTYRCRGFHPHSPTEWSAPSNPLVIMVT
  GLYEKPSLTARPGPTVRAGENVTLSCSSQSSFDIYHLSREGEAHELRLPAVPSINGTFQA
  DFPLGPATHGETYRCFGSFHGSPYEWSDPSDPLPVSVTGNPSSSWPSPTEPSFKTGIARH
  LHAVIRYSVAIILFTILPFFLLHRWCSKKKDAAVMNQEPAGHRTVNREDSDEQDPQEVTY
  AQLDHCIFTQRKITGPSQRSKRPSTDTSVCIELPNAEPRALSPAHEHHSQALMGSSRETT
  ALSQTQLASSNVPAAGI
• Function: Receptor for non-classical major histocompatibility class Ib HLA-G molecules. Recognizes HLA-G in complex with B2M/beta-2 microglobulin and a nonamer self-peptide (peptide-bound HLA-G-B2M). In decidual NK cells, binds peptide-bound HLA-G-B2M complex and triggers NK cell senescence-associated secretory phenotype as a molecular switch to promote vascular remodeling and fetal growth in early pregnancy. May play a role in balancing tolerance and antiviral-immunity at maternal-fetal interface by keeping in check the effector functions of NK, CD8+ T cells and B cells. Upon interaction with peptide-bound HLA-G-B2M, initiates signaling from the endosomal compartment leading to downstream activation of PRKDC-XRCC5 and AKT1, and ultimately triggering NF-kappa-B-dependent pro-inflammatory response.
• Tissue Specificity: Expressed in decidual NK cells and innate lymphoid cell type I (ILC1) . Expressed in a subset of peripheral NK cells .
• KEGG Pathway:
  Cellular senescence (hsa04218)
  Antigen processing and presentation (hsa04612)
• Reactome Pathway: Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Endometriosis	DISX1AG8	Strong	Genetic Variation	[1]
Lupus	DISOKJWA	Strong	Biomarker	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[3]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[2]
Adult lymphoma	DISK8IZR	moderate	Biomarker	[4]
Langerhans cell histiocytosis	DISDQSW3	moderate	Altered Expression	[4]
Langerhans cell histiocytosis specific to childhood	DIS1C04U	moderate	Altered Expression	[4]
Lymphoma	DISN6V4S	moderate	Biomarker	[4]
Mastocytosis	DIS1TEE0	moderate	Biomarker	[4]
Pediatric lymphoma	DIS51BK2	moderate	Biomarker	[4]
Asthma	DISW9QNS	Limited	Genetic Variation	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Killer cell immunoglobulin-like receptor 2DL4 (KIR2DL4).	[6]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Killer cell immunoglobulin-like receptor 2DL4 (KIR2DL4).	[7]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN affects the expression of Killer cell immunoglobulin-like receptor 2DL4 (KIR2DL4).	[9]

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 affects the methylation of Killer cell immunoglobulin-like receptor 2DL4 (KIR2DL4).	[8]

References

• [1] The impact of HLA-G, LILRB1 and LILRB2 gene polymorphisms on susceptibility to and severity of endometriosis.Mol Genet Genomics. 2018 Jun;293(3):601-613. doi: 10.1007/s00438-017-1404-3. Epub 2017 Dec 12.
• [2] Stimulatory and inhibitory killer Ig-like receptor molecules are expressed and functional on lupus T cells.J Immunol. 2009 Sep 1;183(5):3481-7. doi: 10.4049/jimmunol.0900034. Epub 2009 Aug 12.
• [3] Genetic polymorphisms and expression of HLA-G and its receptors, KIR2DL4 and LILRB1, in non-small cell lung cancer.Tissue Antigens. 2015 Jun;85(6):466-75. doi: 10.1111/tan.12561. Epub 2015 Apr 9.
• [4] Killer cell immunoglobulin-like receptor 2DL4 is expressed in and suppresses the cell growth of Langerhans cell histiocytosis.Oncotarget. 2017 Jun 6;8(23):36964-36972. doi: 10.18632/oncotarget.16936.
• [5] Genetic polymorphism of KIR2DL4 (CD158d), a putative NK cell receptor for HLA-G, does not influence susceptibility to asthma.Tissue Antigens. 2013 Oct;82(4):276-9. doi: 10.1111/tan.12185. Epub 2013 Aug 23.
• [6] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [7] DNA methylation inhibition increases T cell KIR expression through effects on both promoter methylation and transcription factors. Clin Immunol. 2009 Feb;130(2):213-24. doi: 10.1016/j.clim.2008.08.009. Epub 2008 Oct 22.
• [8] 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.
• [9] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.