Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUX5TWM)

• DOT Name: HLA class II histocompatibility antigen, DR beta 5 chain (HLA-DRB5)
• Synonyms: DR beta-5; DR2-beta-2; Dw2; MHC class II antigen DRB5
• Gene Name: HLA-DRB5
• Related Disease:
  Tuberculosis
  Advanced cancer
  Allergy
  Autoimmune disease
  Breast cancer
  Breast carcinoma
  Complement component 2 deficiency
  Crohn disease
  Familial Alzheimer disease
  Gastrointestinal mucositis
  Inflammatory bowel disease
  Juvenile idiopathic arthritis
  Neoplasm
  Optic neuritis
  Plasma cell myeloma
  Primary sclerosing cholangitis
  Psoriasis
  Rheumatoid arthritis
  rubella
  Scleroderma
  Sleep disorder
  Staphylococcus aureus infection
  Trichohepatoenteric syndrome
  Type-1 diabetes
  Asthma
  Alzheimer disease
  Amyotrophic lateral sclerosis
  Nervous system inflammation
  Non-insulin dependent diabetes
  Parkinson disease
  Schizophrenia
  Systemic sclerosis
• UniProt ID: DRB5_HUMAN
• PDB ID: 1FV1; 1H15; 1HQR; 1ZGL
• Pfam ID: PF07654 ; PF00969
• Sequence:
  MVCLKLPGGSYMAKLTVTLMVLSSPLALAGDTRPRFLQQDKYECHFFNGTERVRFLHRDI
  YNQEEDLRFDSDVGEYRAVTELGRPDAEYWNSQKDFLEDRRAAVDTYCRHNYGVGESFTV
  QRRVEPKVTVYPARTQTLQHHNLLVCSVNGFYPGSIEVRWFRNSQEEKAGVVSTGLIQNG
  DWTFQTLVMLETVPRSGEVYTCQVEHPSVTSPLTVEWRAQSESAQSKMLSGVGGFVLGLL
  FLGAGLFIYFKNQKGHSGLHPTGLVS
• 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

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Tuberculosis	DIS2YIMD	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Allergy	DIS48ZAP	Strong	Biomarker	[3]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[5]
Complement component 2 deficiency	DIS8OWGU	Strong	Biomarker	[6]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[7]
Familial Alzheimer disease	DISE75U4	Strong	Biomarker	[8]
Gastrointestinal mucositis	DIS140OB	Strong	Biomarker	[9]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[10]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[12]
Optic neuritis	DISDYCHC	Strong	Biomarker	[13]
Plasma cell myeloma	DIS0DFZ0	Strong	Altered Expression	[9]
Primary sclerosing cholangitis	DISTH5WJ	Strong	Genetic Variation	[14]
Psoriasis	DIS59VMN	Strong	Genetic Variation	[7]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[15]
rubella	DISXUI9P	Strong	Biomarker	[16]
Scleroderma	DISVQ342	Strong	Altered Expression	[17]
Sleep disorder	DIS3JP1U	Strong	Biomarker	[18]
Staphylococcus aureus infection	DISK6PTH	Strong	Biomarker	[19]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[20]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[21]
Asthma	DISW9QNS	moderate	Genetic Variation	[22]
Alzheimer disease	DISF8S70	Limited	Genetic Variation	[8]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Genetic Variation	[23]
Nervous system inflammation	DISB3X5A	Limited	Biomarker	[24]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[25]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[8]
Schizophrenia	DISSRV2N	Limited	Biomarker	[26]
Systemic sclerosis	DISF44L6	Limited	Genetic Variation	[27]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	HLA class II histocompatibility antigen, DR beta 5 chain (HLA-DRB5) increases the Liver injury ADR of Aspirin.	[36]
Mitoxantrone	DMM39BF	Approved	HLA class II histocompatibility antigen, DR beta 5 chain (HLA-DRB5) affects the response to substance of Mitoxantrone.	[37]
Lumiracoxib	DM1S4AG	Approved	HLA class II histocompatibility antigen, DR beta 5 chain (HLA-DRB5) affects the response to substance of Lumiracoxib.	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of HLA class II histocompatibility antigen, DR beta 5 chain (HLA-DRB5).	[28]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of HLA class II histocompatibility antigen, DR beta 5 chain (HLA-DRB5).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of HLA class II histocompatibility antigen, DR beta 5 chain (HLA-DRB5).	[34]

5 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of HLA class II histocompatibility antigen, DR beta 5 chain (HLA-DRB5).	[30]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of HLA class II histocompatibility antigen, DR beta 5 chain (HLA-DRB5).	[31]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of HLA class II histocompatibility antigen, DR beta 5 chain (HLA-DRB5).	[32]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of HLA class II histocompatibility antigen, DR beta 5 chain (HLA-DRB5).	[33]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of HLA class II histocompatibility antigen, DR beta 5 chain (HLA-DRB5).	[35]

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