Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDIOB63)

• DOT Name: Interleukin-21 receptor (IL21R)
• Synonyms: IL-21 receptor; IL-21R; Novel interleukin receptor; CD antigen CD360
• Gene Name: IL21R
• Related Disease:
  Immunodeficiency
  Cryptosporidiosis-chronic cholangitis-liver disease syndrome
• UniProt ID: IL21R_HUMAN
• PDB ID: 3TGX; 4NZD; 6PLH; 7KQ7; 8ENT
• Sequence:
  MPRGWAAPLLLLLLQGGWGCPDLVCYTDYLQTVICILEMWNLHPSTLTLTWQDQYEELKD
  EATSCSLHRSAHNATHATYTCHMDVFHFMADDIFSVNITDQSGNYSQECGSFLLAESIKP
  APPFNVTVTFSGQYNISWRSDYEDPAFYMLKGKLQYELQYRNRGDPWAVSPRRKLISVDS
  RSVSLLPLEFRKDSSYELQVRAGPMPGSSYQGTWSEWSDPVIFQTQSEELKEGWNPHLLL
  LLLLVIVFIPAFWSLKTHPLWRLWKKIWAVPSPERFFMPLYKGCSGDFKKWVGAPFTGSS
  LELGPWSPEVPSTLEVYSCHPPRSPAKRLQLTELQEPAELVESDGVPKPSFWPTAQNSGG
  SAYSEERDRPYGLVSIDTVTVLDAEGPCTWPCSCEDDGYPALDLDAGLEPSPGLEDPLLD
  AGTTVLSCGCVSAGSPGLGGPLGSLLDRLKPPLADGEDWAGGLPWGGRSPGGVSESEAGS
  PLAGLDMDTFDSGFVGSDCSSPVECDFTSPGDEGPPRSYLRQWVVIPPPLSSPGPQAS
• Function: This is a receptor for interleukin-21.
• Tissue Specificity: Selectively expressed in lymphoid tissues. Most highly expressed in thymus and spleen.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  JAK-STAT sig.ling pathway (hsa04630)
  Th17 cell differentiation (hsa04659)
  Inflammatory bowel disease (hsa05321)
• Reactome Pathway: Interleukin-21 signaling (R-HSA-9020958)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Immunodeficiency	DIS093I0	Definitive	Autosomal recessive	[1]
Cryptosporidiosis-chronic cholangitis-liver disease syndrome	DISUXDZH	Strong	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Interleukin-21 receptor (IL21R).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Interleukin-21 receptor (IL21R).	[4]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Interleukin-21 receptor (IL21R).	[5]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Interleukin-21 receptor (IL21R).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Interleukin-21 receptor (IL21R).	[7]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Interleukin-21 receptor (IL21R).	[8]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome. J Exp Med. 2013 Mar 11;210(3):433-43. doi: 10.1084/jem.20111229. Epub 2013 Feb 25.
• [3] 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.
• [4] 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.
• [5] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [6] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [7] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.