Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZU3XX7)

• DOT Name: Major histocompatibility complex class I-related gene protein (MR1)
• Synonyms: MHC class I-related gene protein; Class I histocompatibility antigen-like protein
• Gene Name: MR1
• Related Disease:
  Hepatitis B virus infection
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Kidney neoplasm
  Neoplasm
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Tuberculosis
  Ulcerative colitis
  Breast cancer
  Breast carcinoma
  Pancreatic cancer
• UniProt ID: HMR1_HUMAN
• PDB ID: 4GUP ; 4L4T ; 4L4V ; 4LCW ; 4NQC ; 4NQD ; 4NQE ; 4PJ5 ; 4PJ7 ; 4PJ8 ; 4PJ9 ; 4PJA ; 4PJB ; 4PJC ; 4PJD ; 4PJE ; 4PJF ; 4PJG ; 4PJH ; 4PJI ; 4PJX ; 5D5M ; 5D7I ; 5D7J ; 5D7L ; 5U16 ; 5U17 ; 5U1R ; 5U2V ; 5U6Q ; 5U72 ; 6MWR ; 6PUC ; 6PUD ; 6PUE ; 6PUF ; 6PUG ; 6PUH ; 6PUI ; 6PUJ ; 6PUK ; 6PUL ; 6PUM ; 6PVC ; 6PVD ; 6W9U ; 6W9V ; 6XQP ; 7LLI ; 7LLJ ; 7RNO ; 7UFJ ; 7UMG ; 7ZT2 ; 7ZT3 ; 7ZT4 ; 7ZT5 ; 7ZT7 ; 7ZT8 ; 7ZT9 ; 8BP6
• Pfam ID: PF07654 ; PF00129
• Sequence:
  MGELMAFLLPLIIVLMVKHSDSRTHSLRYFRLGVSDPIHGVPEFISVGYVDSHPITTYDS
  VTRQKEPRAPWMAENLAPDHWERYTQLLRGWQQMFKVELKRLQRHYNHSGSHTYQRMIGC
  ELLEDGSTTGFLQYAYDGQDFLIFNKDTLSWLAVDNVAHTIKQAWEANQHELLYQKNWLE
  EECIAWLKRFLEYGKDTLQRTEPPLVRVNRKETFPGVTALFCKAHGFYPPEIYMTWMKNG
  EEIVQEIDYGDILPSGDGTYQAWASIELDPQSSNLYSCHVEHCGVHMVLQVPQESETIPL
  VMKAVSGSIVLVIVLAGVGVLVWRRRPREQNGAIYLPTPDR
• Function: Antigen-presenting molecule specialized in displaying microbial pyrimidine-based metabolites to alpha-beta T cell receptors (TCR) on innate-type mucosal-associated invariant T (MAIT) cells. In complex with B2M preferentially presents riboflavin-derived metabolites to semi-invariant TRAV1-2 TCRs on MAIT cells, guiding immune surveillance of the microbial metabolome at mucosal epithelial barriers. Signature pyrimidine-based microbial antigens are generated via non-enzymatic condensation of metabolite intermediates of the riboflavin pathway with by-products arising from other metabolic pathways such as glycolysis. Typical potent antigenic metabolites are 5-(2-oxoethylideneamino)-6-D-ribitylaminouracil (5-OE-RU) and 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), products of condensation of 5-amino-6-D-ribityaminouracil (5-A-RU) with glyoxal or methylglyoxal by-products, respectively. May present microbial antigens to various TRAV1-2-negative MAIT cell subsets, providing for unique recognition of diverse microbes, including pathogens that do not synthesize riboflavin. Upon antigen recognition, elicits rapid innate-type MAIT cell activation to eliminate pathogenic microbes by directly killing infected cells. During T cell development, drives thymic selection and post-thymic terminal differentiation of MAIT cells in a process dependent on commensal microflora. Acts as an immune sensor of cancer cell metabolome. May present a tumor-specific or -associated metabolite essential for cancer cell survival to a pan-cancer TCR consisting of TRAV38.2-DV8*TRAJ31 alpha chain paired with a TRBV25.1*TRBJ2.3 beta chain on a non-MAIT CD8-positive T cell clone (MC.7.G5), triggering T cell-mediated killing of a wide range of cancer cell types.
• Tissue Specificity: Ubiquitous . Low expression is detected in peripheral blood B cells, T cells, monocytes and in bronchial epithelial cells (at protein level) . Expressed in plasmablasts or plasma B cells in the lamina propria of ileum, appendix and colon (at protein level) . Highly expressed on a subset of CD45-positive CD3-positive thymocytes (at protein level) .

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatitis B virus infection	DISLQ2XY	Strong	Genetic Variation	[1]
Hepatitis C virus infection	DISQ0M8R	Strong	Genetic Variation	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[1]
Kidney neoplasm	DISBNZTN	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Thyroid cancer	DIS3VLDH	Strong	Altered Expression	[4]
Thyroid gland carcinoma	DISMNGZ0	Strong	Altered Expression	[4]
Thyroid tumor	DISLVKMD	Strong	Altered Expression	[4]
Tuberculosis	DIS2YIMD	Strong	Genetic Variation	[5]
Ulcerative colitis	DIS8K27O	Strong	Genetic Variation	[6]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[7]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[7]
Pancreatic cancer	DISJC981	Limited	Altered Expression	[8]

37 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 Major histocompatibility complex class I-related gene protein (MR1).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Major histocompatibility complex class I-related gene protein (MR1).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Major histocompatibility complex class I-related gene protein (MR1).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Major histocompatibility complex class I-related gene protein (MR1).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Major histocompatibility complex class I-related gene protein (MR1).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Major histocompatibility complex class I-related gene protein (MR1).	[14]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Major histocompatibility complex class I-related gene protein (MR1).	[16]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Major histocompatibility complex class I-related gene protein (MR1).	[17]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Major histocompatibility complex class I-related gene protein (MR1).	[18]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Major histocompatibility complex class I-related gene protein (MR1).	[19]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Major histocompatibility complex class I-related gene protein (MR1).	[20]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Major histocompatibility complex class I-related gene protein (MR1).	[21]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Major histocompatibility complex class I-related gene protein (MR1).	[18]
Piroxicam	DMTK234	Approved	Piroxicam affects the expression of Major histocompatibility complex class I-related gene protein (MR1).	[18]
Clozapine	DMFC71L	Approved	Clozapine affects the expression of Major histocompatibility complex class I-related gene protein (MR1).	[18]
Rifampicin	DM5DSFZ	Approved	Rifampicin affects the expression of Major histocompatibility complex class I-related gene protein (MR1).	[18]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of Major histocompatibility complex class I-related gene protein (MR1).	[21]
Zidovudine	DM4KI7O	Approved	Zidovudine affects the expression of Major histocompatibility complex class I-related gene protein (MR1).	[18]
Ifosfamide	DMCT3I8	Approved	Ifosfamide affects the expression of Major histocompatibility complex class I-related gene protein (MR1).	[18]
Gefitinib	DM15F0X	Approved	Gefitinib affects the expression of Major histocompatibility complex class I-related gene protein (MR1).	[18]
Rofecoxib	DM3P5DA	Approved	Rofecoxib affects the expression of Major histocompatibility complex class I-related gene protein (MR1).	[18]
Sulfasalazine	DMICA9H	Approved	Sulfasalazine affects the expression of Major histocompatibility complex class I-related gene protein (MR1).	[18]
Mefenamic acid	DMK7HFI	Approved	Mefenamic acid affects the expression of Major histocompatibility complex class I-related gene protein (MR1).	[18]
Bupropion	DM5PCS7	Approved	Bupropion affects the expression of Major histocompatibility complex class I-related gene protein (MR1).	[18]
Hydrochlorothiazide	DMUSZHD	Approved	Hydrochlorothiazide affects the expression of Major histocompatibility complex class I-related gene protein (MR1).	[18]
Aciclovir	DMYLOVR	Approved	Aciclovir affects the expression of Major histocompatibility complex class I-related gene protein (MR1).	[18]
Norfloxacin	DMIZ6W2	Approved	Norfloxacin affects the expression of Major histocompatibility complex class I-related gene protein (MR1).	[18]
Repaglinide	DM5SXUV	Approved	Repaglinide affects the expression of Major histocompatibility complex class I-related gene protein (MR1).	[18]
Vancomycin	DM3JFIH	Approved	Vancomycin affects the expression of Major histocompatibility complex class I-related gene protein (MR1).	[18]
Lincomycin	DMVTHER	Approved	Lincomycin affects the expression of Major histocompatibility complex class I-related gene protein (MR1).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Major histocompatibility complex class I-related gene protein (MR1).	[22]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Major histocompatibility complex class I-related gene protein (MR1).	[23]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Major histocompatibility complex class I-related gene protein (MR1).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Major histocompatibility complex class I-related gene protein (MR1).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Major histocompatibility complex class I-related gene protein (MR1).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Major histocompatibility complex class I-related gene protein (MR1).	[26]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Major histocompatibility complex class I-related gene protein (MR1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Major histocompatibility complex class I-related gene protein (MR1).	[15]

References

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• [2] Expression and clinical value of the soluble major histocompatibility complex class I-related chain A molecule in the serum of patients with renal tumors.Genet Mol Res. 2015 Jun 29;14(2):7233-40. doi: 10.4238/2015.June.29.16.
• [3] Membrane-bound versus soluble major histocompatibility complex Class I-related chain A and major histocompatibility complex Class I-related chain B differential expression: Mechanisms of tumor eradication versus evasion and current drug development strategies.J Cancer Res Ther. 2016 Oct-Dec;12(4):1224-1233. doi: 10.4103/0973-1482.176169.
• [4] Clinicopathological significance of major histocompatibility complex class I-related chain a and B expression in thyroid cancer.J Clin Endocrinol Metab. 2006 Jul;91(7):2704-12. doi: 10.1210/jc.2006-0492. Epub 2006 Apr 18.
• [5] A polymorphism in human MR1 is associated with mRNA expression and susceptibility to tuberculosis.Genes Immun. 2017 Jan;18(1):8-14. doi: 10.1038/gene.2016.41. Epub 2016 Nov 24.
• [6] Role of major histocompatibility complex class I-related molecules A*A5.1 allele in ulcerative colitis in Chinese patients.Immunology. 2009 Sep;128(1 Suppl):e230-6. doi: 10.1111/j.1365-2567.2008.02953.x. Epub 2008 Nov 7.
• [7] Assessment of changes in expression and presentation of NKG2D under influence of MICA serum factor in different stages of breast cancer.Tumour Biol. 2016 May;37(5):6953-62. doi: 10.1007/s13277-015-4584-7. Epub 2015 Dec 11.
• [8] Low-dose gemcitabine induces major histocompatibility complex class I-related chain A/B expression and enhances an antitumor innate immune response in pancreatic cancer.Clin Exp Med. 2017 Feb;17(1):19-31. doi: 10.1007/s10238-015-0394-x. Epub 2015 Oct 8.
• [9] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [10] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [11] 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.
• [12] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [13] 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.
• [14] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [15] Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood. Epigenetics. 2014 May;9(5):774-82. doi: 10.4161/epi.28153. Epub 2014 Feb 13.
• [16] 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.
• [17] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [18] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [19] 5-Fluorouracil up-regulates interferon pathway gene expression in esophageal cancer cells. Anticancer Res. 2005 Sep-Oct;25(5):3271-8.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [21] Genomic profiling uncovers a molecular pattern for toxicological characterization of mutagens and promutagens in vitro. Toxicol Sci. 2011 Jul;122(1):185-97.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer. Toxicol Appl Pharmacol. 2015 Jun 1;285(2):79-88.
• [24] 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.
• [25] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [26] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.