Details of Drug Off-Target (DOT)

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

• DOT Name: Lymphocyte activation gene 3 protein (LAG3)
• Synonyms: LAG-3; CD antigen CD223
• Gene Name: LAG3
• UniProt ID: LAG3_HUMAN
• PDB ID: 7TZG; 7TZH; 7UM3; 8SO3; 8SR0
• Sequence:
  MWEAQFLGLLFLQPLWVAPVKPLQPGAEVPVVWAQEGAPAQLPCSPTIPLQDLSLLRRAG
  VTWQHQPDSGPPAAAPGHPLAPGPHPAAPSSWGPRPRRYTVLSVGPGGLRSGRLPLQPRV
  QLDERGRQRGDFSLWLRPARRADAGEYRAAVHLRDRALSCRLRLRLGQASMTASPPGSLR
  ASDWVILNCSFSRPDRPASVHWFRNRGQGRVPVRESPHHHLAESFLFLPQVSPMDSGPWG
  CILTYRDGFNVSIMYNLTVLGLEPPTPLTVYAGAGSRVGLPCRLPAGVGTRSFLTAKWTP
  PGGGPDLLVTGDNGDFTLRLEDVSQAQAGTYTCHIHLQEQQLNATVTLAIITVTPKSFGS
  PGSLGKLLCEVTPVSGQERFVWSSLDTPSQRSFSGPWLEAQEAQLLSQPWQCQLYQGERL
  LGAAVYFTELSSPGAQRSGRAPGALPAGHLLLFLILGVLSLLLLVTGAFGFHLWRRQWRP
  RRFSALEQGIHPPQAQSKIEELEQEPEPEPEPEPEPEPEPEPEQL
• Function: Lymphocyte activation gene 3 protein: Inhibitory receptor on antigen activated T-cells. Delivers inhibitory signals upon binding to ligands, such as FGL1. FGL1 constitutes a major ligand of LAG3 and is responsible for LAG3 T-cell inhibitory function. Following TCR engagement, LAG3 associates with CD3-TCR in the immunological synapse and directly inhibits T-cell activation. May inhibit antigen-specific T-cell activation in synergy with PDCD1/PD-1, possibly by acting as a coreceptor for PDCD1/PD-1. Negatively regulates the proliferation, activation, effector function and homeostasis of both CD8(+) and CD4(+) T-cells. Also mediates immune tolerance: constitutively expressed on a subset of regulatory T-cells (Tregs) and contributes to their suppressive function. Also acts as a negative regulator of plasmacytoid dendritic cell (pDCs) activation. Binds MHC class II (MHC-II); the precise role of MHC-II-binding is however unclear ; [Secreted lymphocyte activation gene 3 protein]: May function as a ligand for MHC class II (MHC-II) on antigen-presenting cells (APC), promoting APC activation/maturation and driving Th1 immune response.
• Tissue Specificity: Primarily expressed in activated T-cells and a subset of natural killer (NK) cells.
• Reactome Pathway: MHC class II antigen presentation (R-HSA-2132295)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Lymphocyte activation gene 3 protein (LAG3).	[1]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Lymphocyte activation gene 3 protein (LAG3).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Lymphocyte activation gene 3 protein (LAG3).	[3]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Lymphocyte activation gene 3 protein (LAG3).	[4]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Lymphocyte activation gene 3 protein (LAG3).	[6]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Lymphocyte activation gene 3 protein (LAG3).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Lymphocyte activation gene 3 protein (LAG3).	[5]

References

• [1] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [2] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [3] Fetal-sex dependent genomic responses in the circulating lymphocytes of arsenic-exposed pregnant women in New Hampshire. Reprod Toxicol. 2017 Oct;73:184-195. doi: 10.1016/j.reprotox.2017.07.023. Epub 2017 Aug 6.
• [4] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [5] 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.
• [6] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [7] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.