Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV38BUJ)

• DOT Name: HLA class I histocompatibility antigen, C alpha chain (HLA-C)
• Synonyms: HLA-C; HLA-Cw; Human leukocyte antigen C
• Gene Name: HLA-C
• Related Disease:
  Hepatocellular carcinoma
  Melanoma
  Palmoplantar pustulosis
  Skin disease
  Acute myelogenous leukaemia
  Arteriosclerosis
  Atherosclerosis
  Behcet disease
  Cardiac failure
  Chronic hepatitis B virus infection
  Coeliac disease
  Colorectal carcinoma
  Congestive heart failure
  Crohn disease
  Cytomegalovirus infection
  Glioma
  Graft-versus-host disease
  Graves disease
  Hashimoto thyroiditis
  Hepatitis B virus infection
  Human papillomavirus infection
  Hypertrophic cardiomyopathy
  Idiopathic inflammatory myopathy
  Influenza
  leukaemia
  MHC class II deficiency
  Multiple sclerosis
  Nasopharyngeal carcinoma
  Neoplasm
  Neuroblastoma
  Sarcoidosis
  Squamous cell carcinoma
  Stevens-Johnson syndrome
  Toxic epidermal necrolysis
  Tuberculosis
  Type-1 diabetes
  Type-1/2 diabetes
  Breast cancer
  Breast carcinoma
  Burkitt lymphoma
  Non-small-cell lung cancer
  Arthritis
  Chronic graft versus host disease
  Kaposi sarcoma
  Malignant glioma
  Mixed glioma
  Systemic lupus erythematosus
  Systemic sclerosis
• UniProt ID: HLAC_HUMAN
• PDB ID: 1EFX; 1IM9; 1QQD; 3BZF; 4NT6; 5VGD; 5VGE; 5W67; 5W69; 5W6A; 6JTO; 6PA1; 6PAG
• Pfam ID: PF07654 ; PF00129 ; PF06623
• Sequence:
  MRVMAPRALLLLLSGGLALTETWACSHSMRYFDTAVSRPGRGEPRFISVGYVDDTQFVRF
  DSDAASPRGEPRAPWVEQEGPEYWDRETQKYKRQAQADRVSLRNLRGYYNQSEDGSHTLQ
  RMSGCDLGPDGRLLRGYDQSAYDGKDYIALNEDLRSWTAADTAAQITQRKLEAARAAEQL
  RAYLEGTCVEWLRRYLENGKETLQRAEPPKTHVTHHPLSDHEATLRCWALGFYPAEITLT
  WQRDGEDQTQDTELVETRPAGDGTFQKWAAVVVPSGQEQRYTCHMQHEGLQEPLTLSWEP
  SSQPTIPIMGIVAGLAVLVVLAVLGAVVTAMMCRRKSSGGKGGSCSQAACSNSAQGSDES
  LITCKA
• Function: Antigen-presenting major histocompatibility complex class I (MHCI) molecule with an important role in reproduction and antiviral immunity. In complex with B2M/beta 2 microglobulin displays a restricted repertoire of self and viral peptides and acts as a dominant ligand for inhibitory and activating killer immunoglobulin receptors (KIRs) expressed on NK cells. In an allogeneic setting, such as during pregnancy, mediates interaction of extravillous trophoblasts with KIR on uterine NK cells and regulate trophoblast invasion necessary for placentation and overall fetal growth. During viral infection, may present viral peptides with low affinity for KIRs, impeding KIR-mediated inhibition through peptide antagonism and favoring lysis of infected cells. Presents a restricted repertoire of viral peptides on antigen-presenting cells for recognition by alpha-beta T cell receptor (TCR) on HLA-C-restricted CD8-positive T cells, guiding antigen-specific T cell immune response to eliminate infected cells, particularly in chronic viral infection settings such as HIV-1 or CMV infection. Both the peptide and the MHC molecule are recognized by TCR, the peptide is responsible for the fine specificity of antigen recognition and MHC residues account for the MHC restriction of T cells. Typically presents intracellular peptide antigens of 9 amino acids that arise from cytosolic proteolysis via proteasome. Can bind different peptides containing allele-specific binding motifs, which are mainly defined by anchor residues at position 2 and 9. Preferentially displays peptides having a restricted repertoire of hydrophobic or aromatic amino acids (Phe, Ile, Leu, Met, Val and Tyr) at the C-terminal anchor ; ALLELE C*01:02: The peptide-bound form interacts with KIR2DL2 and KIR2DL3 inhibitory receptors on NK cells. The low affinity peptides compete with the high affinity peptides impeding KIR-mediated inhibition and favoring lysis of infected cells. Presents to CD8-positive T cells a CMV epitope derived from UL83/pp65 (RCPEMISVL), an immediate-early antigen necessary for initiating viral replication ; ALLELE C*04:01: Presents a conserved HIV-1 epitope derived from env (SFNCGGEFF) to memory CD8-positive T cells, eliciting very strong IFNG responses. Presents CMV epitope derived from UL83/pp65 (QYDPVAALF) to CD8-positive T cells, triggering T cell cytotoxic response ; ALLELE C*05:01: Presents HIV-1 epitope derived from rev (SAEPVPLQL) to CD8-positive T cells, triggering T cell cytotoxic response; ALLELE C*06:02: In trophoblasts, interacts with KIR2DS2 on uterine NK cells and triggers NK cell activation, including secretion of cytokines such as GMCSF that enhances trophoblast migration; ALLELE C*07:02: Plays an important role in the control of chronic CMV infection. Presents immunodominant CMV epitopes derived from IE1 (LSEFCRVL and CRVLCCYVL) and UL28 (FRCPRRFCF), both antigens synthesized during immediate-early period of viral replication. Elicits a strong anti-viral CD8-positive T cell immune response that increases markedly with age; ALLELE C*08:01: Presents viral epitopes derived from CMV UL83 (VVCAHELVC) and IAV M1 (GILGFVFTL), triggering CD8-positive T cell cytotoxic response; ALLELE C*12:02: Presents CMV epitope derived from UL83 (VAFTSHEHF) to CD8-positive T cells; ALLELE C*15:02: Presents CMV epitope derived from UL83 CC (VVCAHELVC) to CD8-positive T cells, triggering T cell cytotoxic response.
• Tissue Specificity: Ubiquitous. Highly expressed in fetal extravillous trophoblasts in the decidua basalis (at protein level).
• 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)
  DAP12 interactions (R-HSA-2172127)
  Neutrophil degranulation (R-HSA-6798695)
  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

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Melanoma	DIS1RRCY	Definitive	Biomarker	[2]
Palmoplantar pustulosis	DISCNSWD	Definitive	Biomarker	[3]
Skin disease	DISDW8R6	Definitive	Genetic Variation	[4]
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[5]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[6]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[6]
Behcet disease	DISSYMBS	Strong	Biomarker	[7]
Cardiac failure	DISDC067	Strong	Biomarker	[8]
Chronic hepatitis B virus infection	DISHL4NT	Strong	Genetic Variation	[9]
Coeliac disease	DISIY60C	Strong	Biomarker	[10]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[11]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[8]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[12]
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[13]
Glioma	DIS5RPEH	Strong	Biomarker	[14]
Graft-versus-host disease	DIS0QADF	Strong	Biomarker	[15]
Graves disease	DISU4KOQ	Strong	Biomarker	[16]
Hashimoto thyroiditis	DIS77CDF	Strong	Altered Expression	[17]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[18]
Human papillomavirus infection	DISX61LX	Strong	Genetic Variation	[19]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Genetic Variation	[20]
Idiopathic inflammatory myopathy	DISGB1BZ	Strong	Altered Expression	[21]
Influenza	DIS3PNU3	Strong	Biomarker	[22]
leukaemia	DISS7D1V	Strong	Biomarker	[23]
MHC class II deficiency	DISWMI0G	Strong	Altered Expression	[24]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[25]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Genetic Variation	[26]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[27]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[28]
Sarcoidosis	DISE5B8Z	Strong	Genetic Variation	[29]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[19]
Stevens-Johnson syndrome	DISZG4YX	Strong	Genetic Variation	[30]
Toxic epidermal necrolysis	DISIWPFR	Strong	Biomarker	[31]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[32]
Type-1 diabetes	DIS7HLUB	Strong	Biomarker	[33]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[34]
Breast cancer	DIS7DPX1	moderate	Genetic Variation	[35]
Breast carcinoma	DIS2UE88	moderate	Genetic Variation	[35]
Burkitt lymphoma	DIS9D5XU	moderate	SusceptibilityMutation	[36]
Non-small-cell lung cancer	DIS5Y6R9	Disputed	Altered Expression	[37]
Arthritis	DIST1YEL	Limited	Genetic Variation	[38]
Chronic graft versus host disease	DIS1MM9J	Limited	Biomarker	[39]
Kaposi sarcoma	DISC1H1Z	Limited	Biomarker	[40]
Malignant glioma	DISFXKOV	Limited	Biomarker	[41]
Mixed glioma	DIS64UY3	Limited	Biomarker	[41]
Systemic lupus erythematosus	DISI1SZ7	Limited	Biomarker	[42]
Systemic sclerosis	DISF44L6	Limited	Biomarker	[43]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Carbamazepine	DMZOLBI	Approved	HLA class I histocompatibility antigen, C alpha chain (HLA-C) increases the Rash macular ADR of Carbamazepine.	[70]
Phenytoin	DMNOKBV	Approved	HLA class I histocompatibility antigen, C alpha chain (HLA-C) increases the Toxic epidermal necrolysis ADR of Phenytoin.	[71]
Allopurinol	DMLPAOB	Approved	HLA class I histocompatibility antigen, C alpha chain (HLA-C) increases the Toxic epidermal necrolysis ADR of Allopurinol.	[72]
Ticlopidine	DMO946V	Approved	HLA class I histocompatibility antigen, C alpha chain (HLA-C) increases the Liver injury ADR of Ticlopidine.	[73]

25 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, C alpha chain (HLA-C).	[44]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[45]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[46]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[47]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[48]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[49]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[50]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[52]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[53]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[54]
Selenium	DM25CGV	Approved	Selenium increases the expression of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[55]
Menadione	DMSJDTY	Approved	Menadione affects the expression of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[56]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[57]
Mitomycin	DMH0ZJE	Approved	Mitomycin decreases the expression of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[58]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[59]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[54]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[46]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[55]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[63]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[64]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[65]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[66]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[67]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[68]
	DM9CEI5		decreases the expression of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[69]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[51]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[62]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Abacavir	DMMN36E	Approved	Abacavir affects the binding of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[60]
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of HLA class I histocompatibility antigen, C alpha chain (HLA-C).	[61]

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