Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMYLOV4)

DOT Name	Natural killer cells antigen CD94 (KLRD1)
Synonyms	KP43; Killer cell lectin-like receptor subfamily D member 1; NK cell receptor; CD antigen CD94
Gene Name	KLRD1
Related Disease	Cytomegalovirus infection ( ) Acute myelogenous leukaemia ( ) Autoimmune disease ( ) Chikungunya virus infection ( ) Hepatitis B virus infection ( ) Hepatocellular carcinoma ( ) HIV infectious disease ( ) Idiopathic thrombocytopenic purpura ( ) Lymphoproliferative syndrome ( ) Multiple sclerosis ( ) Neoplasm ( ) Non-small-cell lung cancer ( ) Promyelocytic leukaemia ( ) Rheumatoid arthritis ( ) Spastic paralysis ( ) Systemic lupus erythematosus ( ) Von hippel-lindau disease ( ) Bacterial infection ( ) Chronic graft versus host disease ( ) Chronic hepatitis B virus infection ( ) Influenza ( ) Metastatic malignant neoplasm ( ) Extranodal NK/T-cell Lymphoma ( ) Adult lymphoma ( ) Asthma ( ) Graft-versus-host disease ( ) Hepatitis C virus infection ( ) Human papillomavirus infection ( ) Lymphoma ( ) Pediatric lymphoma ( ) Type-1 diabetes ( )
UniProt ID	KLRD1_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	1B6E; 3BDW; 3CDG; 3CII
Pfam ID	PF00059
Sequence	MAVFKTTLWRLISGTLGIICLSLMSTLGILLKNSFTKLSIEPAFTPGPNIELQKDSDCCS CQEKWVGYRCNCYFISSEQKTWNESRHLCASQKSSLLQLQNTDELDFMSSSQQFYWIGLS YSEEHTAWLWENGSALSQYLFPSFETFNTKNCIAYNPNGNALDESCEDKNRYICKQQLI
Function	Immune receptor involved in self-nonself discrimination. In complex with KLRC1 or KLRC2 on cytotoxic and regulatory lymphocyte subsets, recognizes non-classical major histocompatibility (MHC) class Ib molecule HLA-E loaded with self-peptides derived from the signal sequence of classical MHC class Ia and non-classical MHC class Ib molecules. Enables cytotoxic cells to monitor the expression of MHC class I molecules in healthy cells and to tolerate self. Primarily functions as a ligand binding subunit as it lacks the capacity to signal; KLRD1-KLRC1 acts as an immune inhibitory receptor. Key inhibitory receptor on natural killer (NK) cells that regulates their activation and effector functions. Dominantly counteracts T cell receptor signaling on a subset of memory/effector CD8-positive T cells as part of an antigen-driven response to avoid autoimmunity. On intraepithelial CD8-positive gamma-delta regulatory T cells triggers TGFB1 secretion, which in turn limits the cytotoxic programming of intraepithelial CD8-positive alpha-beta T cells, distinguishing harmless from pathogenic antigens. In HLA-E-rich tumor microenvironment, acts as an immune inhibitory checkpoint and may contribute to progressive loss of effector functions of NK cells and tumor-specific T cells, a state known as cell exhaustion. Upon HLA-E-peptide binding, transmits intracellular signals through KLRC1 immunoreceptor tyrosine-based inhibition motifs (ITIMs) by recruiting INPP5D/SHIP-1 and INPPL1/SHIP-2 tyrosine phosphatases to ITIMs, and ultimately opposing signals transmitted by activating receptors through dephosphorylation of proximal signaling molecules ; KLRD1-KLRC2 acts as an immune activating receptor. On cytotoxic lymphocyte subsets recognizes HLA-E loaded with signal sequence-derived peptides from non-classical MHC class Ib HLA-G molecules, likely playing a role in the generation and effector functions of adaptive NK cells and in maternal-fetal tolerance during pregnancy. Regulates the effector functions of terminally differentiated cytotoxic lymphocyte subsets, and in particular may play a role in adaptive NK cell response to viral infection. Upon HLA-E-peptide binding, transmits intracellular signals via the adapter protein TYROBP/DAP12, triggering the phosphorylation of proximal signaling molecules and cell activation ; (Microbial infection) Viruses like human cytomegalovirus have evolved an escape mechanism whereby virus-induced down-regulation of host MHC class I molecules is coupled to the binding of viral peptides to HLA-E, restoring HLA-E expression and inducing HLA-E-dependent NK cell immune tolerance to infected cells. Recognizes HLA-E in complex with human cytomegalovirus UL40-derived peptide (VMAPRTLIL) and inhibits NK cell cytotoxicity; (Microbial infection) May recognize HLA-E in complex with HIV-1 gag/Capsid protein p24-derived peptide (AISPRTLNA) on infected cells and may inhibit NK cell cytotoxicity, a mechanism that allows HIV-1 to escape immune recognition; (Microbial infection) Upon SARS-CoV-2 infection, may contribute to functional exhaustion of cytotoxic NK cells and CD8-positive T cells. On NK cells, may recognize HLA-E in complex with SARS-CoV-2 S/Spike protein S1-derived peptide (LQPRTFLL) expressed on the surface of lung epithelial cells, inducing NK cell exhaustion and dampening antiviral immune surveillance.
Tissue Specificity	Expressed in NK cell subsets (at protein level) . Expressed in memory/effector CD8-positive alpha-beta T cell subsets (at protein level) . Expressed in melanoma-specific cytotoxic T cell clones (at protein level) . Expressed in terminally differentiated cytotoxic gamma-delta T cells (at protein level) . KLRD1-KLRC1 and KLRD1-KLRC2 are differentially expressed in NK and T cell populations, with only minor subsets expressing both receptor complexes (at protein level) .
KEGG Pathway	Antigen processing and presentation (hsa04612 ) .tural killer cell mediated cytotoxicity (hsa04650 ) Graft-versus-host disease (hsa05332 )
Reactome Pathway	DAP12 interactions (R-HSA-2172127 ) DAP12 signaling (R-HSA-2424491 ) Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933 )

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Cytomegalovirus infection	DISCEMGC	Definitive	Altered Expression	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[2]
Autoimmune disease	DISORMTM	Strong	Biomarker	[3]
Chikungunya virus infection	DISDXEHY	Strong	Altered Expression	[4]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
HIV infectious disease	DISO97HC	Strong	Genetic Variation	[6]
Idiopathic thrombocytopenic purpura	DISFKGJU	Strong	Biomarker	[7]
Lymphoproliferative syndrome	DISMVL8O	Strong	Altered Expression	[8]
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[11]
Promyelocytic leukaemia	DISYGG13	Strong	Altered Expression	[12]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[13]
Spastic paralysis	DISVQ6I2	Strong	Biomarker	[14]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[15]
Von hippel-lindau disease	DIS6ZFQQ	Strong	Altered Expression	[16]
Bacterial infection	DIS5QJ9S	moderate	Biomarker	[17]
Chronic graft versus host disease	DIS1MM9J	moderate	Biomarker	[18]
Chronic hepatitis B virus infection	DISHL4NT	moderate	Genetic Variation	[19]
Influenza	DIS3PNU3	moderate	Biomarker	[20]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[21]
Extranodal NK/T-cell Lymphoma	DIS72GCL	Disputed	Biomarker	[22]
Adult lymphoma	DISK8IZR	Limited	Genetic Variation	[23]
Asthma	DISW9QNS	Limited	Genetic Variation	[24]
Graft-versus-host disease	DIS0QADF	Limited	Biomarker	[25]
Hepatitis C virus infection	DISQ0M8R	Limited	Biomarker	[26]
Human papillomavirus infection	DISX61LX	Limited	Genetic Variation	[27]
Lymphoma	DISN6V4S	Limited	Genetic Variation	[23]
Pediatric lymphoma	DIS51BK2	Limited	Genetic Variation	[23]
Type-1 diabetes	DIS7HLUB	Limited	Altered Expression	[28]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorothiazide	DMLHESP	Approved	Natural killer cells antigen CD94 (KLRD1) increases the Metabolic disorder ADR of Chlorothiazide.	[32]
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3 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Natural killer cells antigen CD94 (KLRD1).	[29]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Natural killer cells antigen CD94 (KLRD1).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Natural killer cells antigen CD94 (KLRD1).	[31]
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References

1	Enrichment of Cytomegalovirus-induced NKG2C+ Natural Killer Cells in the Lung Allograft.Transplantation. 2019 Aug;103(8):1689-1699. doi: 10.1097/TP.0000000000002545.
2	KIR and HLA genotypes predictive of low-affinity interactions are associated with lower relapse in autologous hematopoietic cell transplantation for acute myeloid leukemia.J Immunol. 2015 May 1;194(9):4222-30. doi: 10.4049/jimmunol.1402124. Epub 2015 Mar 25.
3	Peptide-specific engagement of the activating NK cell receptor KIR2DS1.Sci Rep. 2017 May 25;7(1):2414. doi: 10.1038/s41598-017-02449-x.
4	Differential inhibitory and activating NK cell receptor levels and NK/NKT-like cell functionality in chronic and recovered stages of chikungunya.PLoS One. 2017 Nov 28;12(11):e0188342. doi: 10.1371/journal.pone.0188342. eCollection 2017.
5	NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma.Cell Mol Immunol. 2015 May;12(3):292-302. doi: 10.1038/cmi.2014.91. Epub 2014 Oct 13.
6	Natural killer (NK) cell receptor-HLA ligand genotype combinations associated with protection from HIV infection: investigation of how protective genotypes influence anti HIV NK cell functions.AIDS Res Ther. 2017 Sep 12;14(1):38. doi: 10.1186/s12981-017-0172-9.
7	NK cell compartment in the peripheral blood and spleen in adult patients with primary immune thrombocytopenia.Clin Immunol. 2017 Apr;177:18-28. doi: 10.1016/j.clim.2015.11.005. Epub 2015 Nov 18.
8	Chronic T-cell lymphoproliferative disease expressing natural killer cell receptors: clinicopathological and molecular features.Cancer Genet Cytogenet. 2001 Sep;129(2):168-72. doi: 10.1016/s0165-4608(01)00451-4.
9	Are natural killer cells involved in multiple sclerosis etiology? Evidences from NKp46/NCR1 receptor modulation in an observational study.J Neurol Sci. 2014 Oct 15;345(1-2):248-51. doi: 10.1016/j.jns.2014.07.045. Epub 2014 Jul 30.
10	Enriched HLA-E and CD94/NKG2A Interaction Limits Antitumor CD8(+) Tumor-Infiltrating T Lymphocyte Responses.Cancer Immunol Res. 2019 Aug;7(8):1293-1306. doi: 10.1158/2326-6066.CIR-18-0885. Epub 2019 Jun 18.
11	Prognostic impact of the expression of NCR1 and NCR3 NK cell receptors and PD-L1 on advanced non-small cell lung cancer.Oncoimmunology. 2016 May 13;6(1):e1163456. doi: 10.1080/2162402X.2016.1163456. eCollection 2017.
12	Multiple layers of heterogeneity and subset diversity in human MAIT cell responses to distinct microorganisms and to innate cytokines.Proc Natl Acad Sci U S A. 2017 Jul 3;114(27):E5434-E5443. doi: 10.1073/pnas.1705759114. Epub 2017 Jun 19.
13	Influence of CD94 and NKG2A variants on susceptibility to rheumatoid arthritis and efficacy of anti-TNF treatment.Joint Bone Spine. 2016 Jan;83(1):75-9. doi: 10.1016/j.jbspin.2015.06.010. Epub 2015 Oct 6.
14	Low frequency of CD94/NKG2A+ T lymphocytes in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis, but not in asymptomatic carriers.Blood. 2003 Jul 15;102(2):577-84. doi: 10.1182/blood-2002-09-2855. Epub 2003 Jan 30.
15	Downregulation of CD94/NKG2A inhibitory receptor on decreased T cells in patients with systemic lupus erythematosus.Scand J Immunol. 2012 Jul;76(1):62-9. doi: 10.1111/j.1365-3083.2012.02705.x.
16	Natural killer (NK) cell lytic dysfunction and putative NK cell receptor expression abnormality in members of a family with chromosome 3p-linked von Hippel-Lindau disease.J Natl Cancer Inst. 1992 Dec 16;84(24):1897-903. doi: 10.1093/jnci/84.24.1897.
17	NCR1-deficiency diminishes the generation of protective murine cytomegalovirus antibodies by limiting follicular helper T-cell maturation.Eur J Immunol. 2017 Sep;47(9):1443-1456. doi: 10.1002/eji.201646763. Epub 2017 Jul 21.
18	The Activating NKG2C Receptor Is Significantly Reduced in NK Cells after Allogeneic Stem Cell Transplantation in Patients with Severe Graft-versus-Host Disease.Int J Mol Sci. 2016 Oct 27;17(11):1797. doi: 10.3390/ijms17111797.
19	Association of NKG2D genetic polymorphism with susceptibility to chronic hepatitis B in a Han Chinese population.J Med Virol. 2010 Sep;82(9):1501-7. doi: 10.1002/jmv.21855.
20	KLRD1-expressing natural killer cells predict influenza susceptibility.Genome Med. 2018 Jun 14;10(1):45. doi: 10.1186/s13073-018-0554-1.
21	Interleukin-12 from CD103(+) Batf3-Dependent Dendritic Cells Required for NK-Cell Suppression of Metastasis.Cancer Immunol Res. 2017 Dec;5(12):1098-1108. doi: 10.1158/2326-6066.CIR-17-0341. Epub 2017 Oct 25.
22	CD94 transcripts imply a better prognosis in nasal-type extranodal NK/T-cell lymphoma.Blood. 2003 Oct 1;102(7):2623-31. doi: 10.1182/blood-2003-01-0295. Epub 2003 Jun 19.
23	A case of lymphoblastoid natural killer (NK)-cell lymphoma: association with the NK-cell receptor complex CD94/NKG2 and TP53 intragenic deletion.Br J Dermatol. 2002 Jan;146(1):148-53. doi: 10.1046/j.0007-0963.2001.04571.x.
24	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.
25	Immune reconstitution and tolerance after allogeneic hematopoietic stem cell transplantation.Hematology. 2003 Feb;8(1):19-26. doi: 10.1080/1024533031000072045.
26	Dual function of the NK cell receptor 2B4 (CD244) in the regulation of HCV-specific CD8+ T cells.PLoS Pathog. 2011 May;7(5):e1002045. doi: 10.1371/journal.ppat.1002045. Epub 2011 May 19.
27	Evaluation of the association of NKG2C copy number variations with susceptibility to human papillomavirus-induced cervical lesions.Hum Immunol. 2013 Oct;74(10):1352-6. doi: 10.1016/j.humimm.2013.07.006. Epub 2013 Jul 31.
28	Low gene expression levels of activating receptors of natural killer cells (NKG2E and CD94) in patients with fulminant type 1 diabetes.Immunol Lett. 2013 Nov-Dec;156(1-2):149-55. doi: 10.1016/j.imlet.2013.10.004. Epub 2013 Oct 25.
29	The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
30	Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
31	Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
32	Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. Pharmacogenomics J. 2014 Feb;14(1):35-40. doi: 10.1038/tpj.2013.3. Epub 2013 Feb 12.