General Information of Drug Off-Target (DOT) (ID: OTC6GISG)

DOT Name HLA class II histocompatibility antigen, DQ alpha 1 chain (HLA-DQA1)
Synonyms DC-1 alpha chain; DC-alpha; HLA-DCA; MHC class II DQA1
Gene Name HLA-DQA1
UniProt ID
DQA1_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
1JK8; 1S9V; 1UVQ; 2NNA; 4GG6; 4OZF; 4OZG; 4OZH; 4OZI; 5KSA; 5KSB; 5KSU; 5KSV; 6MFF; 6MFG; 6U3M; 6U3N; 6XP6; 7SG0; 7SG1; 7SG2; 8W83; 8W84; 8W85; 8W86
Pfam ID
PF07654 ; PF00993
Sequence
MILNKALMLGALALTTVMSPCGGEDIVADHVASYGVNLYQSYGPSGQYTHEFDGDEQFYV
DLGRKETVWCLPVLRQFRFDPQFALTNIAVLKHNLNSLIKRSNSTAATNEVPEVTVFSKS
PVTLGQPNILICLVDNIFPPVVNITWLSNGHSVTEGVSETSFLSKSDHSFFKISYLTLLP
SAEESYDCKVEHWGLDKPLLKHWEPEIPAPMSELTETVVCALGLSVGLVGIVVGTVFIIR
GLRSVGASRHQGPL
Function
Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments, exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides, autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs, other cells of the gastrointestinal tract, such as epithelial cells, express MHC class II molecules and CD74 and act as APCs, which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen, three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs, CD74 undergoes a sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules, increased acidification produces increased proteolysis and efficient peptide loading.
KEGG Pathway
Phagosome (hsa04145 )
Cell adhesion molecules (hsa04514 )
Antigen processing and presentation (hsa04612 )
Hematopoietic cell lineage (hsa04640 )
Th1 and Th2 cell differentiation (hsa04658 )
Th17 cell differentiation (hsa04659 )
Intesti.l immune network for IgA production (hsa04672 )
Type I diabetes mellitus (hsa04940 )
Leishmaniasis (hsa05140 )
Toxoplasmosis (hsa05145 )
Staphylococcus aureus infection (hsa05150 )
Tuberculosis (hsa05152 )
Influenza A (hsa05164 )
Human T-cell leukemia virus 1 infection (hsa05166 )
Herpes simplex virus 1 infection (hsa05168 )
Epstein-Barr virus infection (hsa05169 )
Asthma (hsa05310 )
Autoimmune thyroid disease (hsa05320 )
Inflammatory bowel disease (hsa05321 )
Systemic lupus erythematosus (hsa05322 )
Rheumatoid arthritis (hsa05323 )
Allograft rejection (hsa05330 )
Graft-versus-host disease (hsa05332 )
Viral myocarditis (hsa05416 )
Reactome Pathway
Phosphorylation of CD3 and TCR zeta chains (R-HSA-202427 )
Translocation of ZAP-70 to Immunological synapse (R-HSA-202430 )
Generation of second messenger molecules (R-HSA-202433 )
MHC class II antigen presentation (R-HSA-2132295 )
PD-1 signaling (R-HSA-389948 )
Interferon gamma signaling (R-HSA-877300 )
Downstream TCR signaling (R-HSA-202424 )

Molecular Interaction Atlas (MIA) of This DOT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
This DOT Affected the Drug Response of 5 Drug(s)
Drug Name Drug ID Highest Status Interaction REF
Azathioprine DMMZSXQ Approved HLA class II histocompatibility antigen, DQ alpha 1 chain (HLA-DQA1) affects the response to substance of Azathioprine. [10]
Aspirin DM672AH Approved HLA class II histocompatibility antigen, DQ alpha 1 chain (HLA-DQA1) increases the Liver injury ADR of Aspirin. [11]
Lapatinib DM3BH1Y Approved HLA class II histocompatibility antigen, DQ alpha 1 chain (HLA-DQA1) increases the Hepatotoxicty ADR of Lapatinib. [12]
Mercaptopurine DMTM2IK Approved HLA class II histocompatibility antigen, DQ alpha 1 chain (HLA-DQA1) affects the response to substance of Mercaptopurine. [10]
Lumiracoxib DM1S4AG Approved HLA class II histocompatibility antigen, DQ alpha 1 chain (HLA-DQA1) affects the response to substance of Lumiracoxib. [11]
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7 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Acetaminophen DMUIE76 Approved Acetaminophen increases the expression of HLA class II histocompatibility antigen, DQ alpha 1 chain (HLA-DQA1). [1]
Calcitriol DM8ZVJ7 Approved Calcitriol decreases the expression of HLA class II histocompatibility antigen, DQ alpha 1 chain (HLA-DQA1). [3]
Marinol DM70IK5 Approved Marinol increases the expression of HLA class II histocompatibility antigen, DQ alpha 1 chain (HLA-DQA1). [4]
Dexamethasone DMMWZET Approved Dexamethasone increases the expression of HLA class II histocompatibility antigen, DQ alpha 1 chain (HLA-DQA1). [5]
Testosterone enanthate DMB6871 Approved Testosterone enanthate affects the expression of HLA class II histocompatibility antigen, DQ alpha 1 chain (HLA-DQA1). [6]
Capecitabine DMTS85L Approved Capecitabine decreases the expression of HLA class II histocompatibility antigen, DQ alpha 1 chain (HLA-DQA1). [7]
QUERCITRIN DM1DH96 Investigative QUERCITRIN affects the expression of HLA class II histocompatibility antigen, DQ alpha 1 chain (HLA-DQA1). [9]
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⏷ Show the Full List of 7 Drug(s)
2 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 HLA class II histocompatibility antigen, DQ alpha 1 chain (HLA-DQA1). [2]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of HLA class II histocompatibility antigen, DQ alpha 1 chain (HLA-DQA1). [8]
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References

1 Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
2 Transcriptomics and methylomics of CD4-positive T cells in arsenic-exposed women. Arch Toxicol. 2017 May;91(5):2067-2078. doi: 10.1007/s00204-016-1879-4. Epub 2016 Nov 12.
3 Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
4 Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
5 Glucocorticoid regulation of human eosinophil gene expression. J Steroid Biochem Mol Biol. 2003 Mar;84(4):441-52. doi: 10.1016/s0960-0760(03)00065-7.
6 Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
7 Gene expression responses reflecting 5-FU-induced toxicity: Comparison between patient colon tissue and 3D human colon organoids. Toxicol Lett. 2022 Dec 1;371:17-24. doi: 10.1016/j.toxlet.2022.09.013. Epub 2022 Sep 29.
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.
10 HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants. Nat Genet. 2014 Oct;46(10):1131-4. doi: 10.1038/ng.3093. Epub 2014 Sep 14.
11 A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury. Nat Genet. 2010 Aug;42(8):711-4. doi: 10.1038/ng.632. Epub 2010 Jul 18.
12 HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer. J Clin Oncol. 2011 Feb 20;29(6):667-73. doi: 10.1200/JCO.2010.31.3197. Epub 2011 Jan 18.