Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMLK1KN)

• DOT Name: HLA class I histocompatibility antigen, alpha chain G (HLA-G)
• Synonyms: HLA G antigen; MHC class I antigen G
• Gene Name: HLA-G
• UniProt ID: HLAG_HUMAN
• PDB ID: 1YDP; 2D31; 2DYP; 3BZE; 3CDG; 3CII; 3KYN; 3KYO; 6AEE; 6K60
• Pfam ID: PF07654 ; PF00129
• Sequence:
  MVVMAPRTLFLLLSGALTLTETWAGSHSMRYFSAAVSRPGRGEPRFIAMGYVDDTQFVRF
  DSDSACPRMEPRAPWVEQEGPEYWEEETRNTKAHAQTDRMNLQTLRGYYNQSEASSHTLQ
  WMIGCDLGSDGRLLRGYEQYAYDGKDYLALNEDLRSWTAADTAAQISKRKCEAANVAEQR
  RAYLEGTCVEWLHRYLENGKEMLQRADPPKTHVTHHPVFDYEATLRCWALGFYPAEIILT
  WQRDGEDQTQDVELVETRPAGDGTFQKWAAVVVPSGEEQRYTCHVQHEGLPEPLMLRWKQ
  SSLPTIPIMGIVAGLVVLAAVVTGAAVAAVLWRKKSSD
• Function: [Isoform 1]: Non-classical major histocompatibility class Ib molecule involved in immune regulatory processes at the maternal-fetal interface. In complex with B2M/beta-2 microglobulin binds a limited repertoire of nonamer self-peptides derived from intracellular proteins including histones and ribosomal proteins. Peptide-bound HLA-G-B2M complex acts as a ligand for inhibitory/activating KIR2DL4, LILRB1 and LILRB2 receptors on uterine immune cells to promote fetal development while maintaining maternal-fetal tolerance. Upon interaction with KIR2DL4 and LILRB1 receptors on decidual NK cells, it triggers NK cell senescence-associated secretory phenotype as a molecular switch to promote vascular remodeling and fetal growth in early pregnancy. Through interaction with KIR2DL4 receptor on decidual macrophages induces pro-inflammatory cytokine production mainly associated with tissue remodeling. Through interaction with LILRB2 receptor triggers differentiation of type 1 regulatory T cells and myeloid-derived suppressor cells, both of which actively maintain maternal-fetal tolerance. 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. Reprograms B cells toward an immune suppressive phenotype via LILRB1. May induce immune activation/suppression via intercellular membrane transfer (trogocytosis), likely enabling interaction with KIR2DL4, which resides mostly in endosomes. Through interaction with the inhibitory receptor CD160 on endothelial cells may control angiogenesis in immune privileged sites ; [Isoform 2]: Likely does not bind B2M and presents peptides. Negatively regulates NK cell- and CD8+ T cell-mediated cytotoxicity ; [Isoform 3]: Likely does not bind B2M and presents peptides. Negatively regulates NK cell- and CD8+ T cell-mediated cytotoxicity ; [Isoform 4]: Likely does not bind B2M and presents peptides. Negatively regulates NK cell- and CD8+ T cell-mediated cytotoxicity ; [Isoform 5]: Non-classical major histocompatibility class Ib molecule involved in immune regulatory processes at the maternal-fetal interface. In complex with B2M/beta-2 microglobulin binds a limited repertoire of nonamer self-peptides derived from intracellular proteins including histones and ribosomal proteins. Peptide-bound HLA-G-B2M complex acts as a ligand for inhibitory/activating KIR2DL4, LILRB1 and LILRB2 receptors on uterine immune cells to promote fetal development while maintaining maternal-fetal tolerance. Upon interaction with KIR2DL4 and LILRB1 receptors on decidual NK cells, it triggers NK cell senescence-associated secretory phenotype as a molecular switch to promote vascular remodeling and fetal growth in early pregnancy. Through interaction with KIR2DL4 receptor on decidual macrophages induces pro-inflammatory cytokine production mainly associated with tissue remodeling. Through interaction with LILRB2 receptor triggers differentiation of type 1 regulatory T cells and myeloid-derived suppressor cells, both of which actively maintain maternal-fetal tolerance. Reprograms B cells toward an immune suppressive phenotype via LILRB1 ; [Isoform 6]: Likely does not bind B2M and presents peptides; [Isoform 7]: Likely does not bind B2M and presents peptides.
• Tissue Specificity: Expressed in adult eye . Expressed in immune cell subsets including monocytes, myeloid and plasmacytoid dendritic cells and regulatory T cells (Tr1)(at protein level) . Secreted by follicular dendritic cell and follicular helper T cells .; [Isoform 5]: Detected in physiological fluids including amniotic fluid and serum.; [Isoform 7]: Expressed in placenta, amniotic membrane, skin, cord blood and peripheral blood mononuclear cells.
• KEGG Pathway:
  Endocytosis (hsa04144)
  Phagosome (hsa04145)
  Cellular senescence (hsa04218)
  Cell adhesion molecules (hsa04514)
  Antigen processing and presentation (hsa04612)
  .tural killer cell mediated cytotoxicity (hsa04650)
  Type I diabetes mellitus (hsa04940)
  Human cytomegalovirus infection (hsa05163)
  Human papillomavirus infection (hsa05165)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  Viral carcinogenesis (hsa05203)
  Autoimmune thyroid disease (hsa05320)
  Allograft rejection (hsa05330)
  Graft-versus-host disease (hsa05332)
  Viral myocarditis (hsa05416)
• Reactome Pathway:
  Endosomal/Vacuolar pathway (R-HSA-1236977)
  Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)
  Interferon gamma signaling (R-HSA-877300)
  Interferon alpha/beta signaling (R-HSA-909733)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  Antigen Presentation (R-HSA-983170)
  ER-Phagosome pathway (R-HSA-1236974)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	HLA class I histocompatibility antigen, alpha chain G (HLA-G) affects the response to substance of Cisplatin.	[19]

33 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 HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[9]
Selenium	DM25CGV	Approved	Selenium increases the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[10]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[11]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[12]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[13]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[14]
Rifampicin	DM5DSFZ	Approved	Rifampicin affects the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[7]
Ifosfamide	DMCT3I8	Approved	Ifosfamide affects the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[7]
Ciprofloxacin XR	DM2NLS9	Approved	Ciprofloxacin XR affects the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[7]
Omeprazole	DM471KJ	Approved	Omeprazole affects the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[7]
Erythromycin	DM4K7GQ	Approved	Erythromycin affects the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[7]
Pyrimethamine	DM5X7VY	Approved	Pyrimethamine affects the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[7]
Glimepiride	DM5FSJA	Approved	Glimepiride affects the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[7]
Sulfamethoxazole	DMB08GE	Approved	Sulfamethoxazole affects the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[7]
Ketorolac	DMI4EL5	Approved	Ketorolac affects the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[7]
Bumetanide	DMRV7H0	Approved	Bumetanide affects the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[7]
Cefadroxil	DMMC345	Approved	Cefadroxil affects the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[7]
Meropenem	DM62UHC	Approved	Meropenem affects the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[6]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[3]
OSI-906	DMHKZLF	Phase 3	OSI-906 decreases the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[15]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[17]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[18]
Lisinopril	DMUOK4C	Investigative	Lisinopril affects the expression of HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[7]

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 HLA class I histocompatibility antigen, alpha chain G (HLA-G).	[16]

References

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• [4] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [5] Changes in gene expression profiles of multiple myeloma cells induced by arsenic trioxide (ATO): possible mechanisms to explain ATO resistance in vivo. Br J Haematol. 2005 Mar;128(5):636-44.
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• [9] Modulation of HLA-G expression. Neoplasma. 2007;54(6):455-62.
• [10] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [11] Progesterone enhances HLA-G gene expression in JEG-3 choriocarcinoma cells and human cytotrophoblasts in vitro. Hum Reprod. 2006 Jan;21(1):46-51. doi: 10.1093/humrep/dei305. Epub 2005 Oct 6.
• [12] 5-Fluorouracil up-regulates interferon pathway gene expression in esophageal cancer cells. Anticancer Res. 2005 Sep-Oct;25(5):3271-8.
• [13] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [14] DNA array analysis of the effects of aspirin on colon cancer cells: involvement of Rac1. Carcinogenesis. 2004 Jul;25(7):1293-8.
• [15] Screening of Organophosphate Flame Retardants with Placentation-Disrupting Effects in Human Trophoblast Organoid Model and Characterization of Adverse Pregnancy Outcomes in Mice. Environ Health Perspect. 2022 May;130(5):57002. doi: 10.1289/EHP10273. Epub 2022 May 3.
• [16] 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.
• [17] Effect of bisphenol A on alterations of ICAM-1 and HLA-G genes expression and DNA methylation profiles in cumulus cells of infertile women with poor response to ovarian stimulation. Sci Rep. 2021 May 5;11(1):9595. doi: 10.1038/s41598-021-87175-1.
• [18] 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.
• [19] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.