Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQWXK71)

• DOT Name: NKG2-D type II integral membrane protein (KLRK1)
• Synonyms: Killer cell lectin-like receptor subfamily K member 1; NK cell receptor D; NKG2-D-activating NK receptor; CD antigen CD314
• Gene Name: KLRK1
• UniProt ID: NKG2D_HUMAN
• PDB ID: 1HYR; 1KCG; 1MPU; 4PDC; 4S0U
• Pfam ID: PF00059
• Sequence:
  MGWIRGRRSRHSWEMSEFHNYNLDLKKSDFSTRWQKQRCPVVKSKCRENASPFFFCCFIA
  VAMGIRFIIMVTIWSAVFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNW
  YESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLT
  IIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTV
• Function: Functions as an activating and costimulatory receptor involved in immunosurveillance upon binding to various cellular stress-inducible ligands displayed at the surface of autologous tumor cells and virus-infected cells. Provides both stimulatory and costimulatory innate immune responses on activated killer (NK) cells, leading to cytotoxic activity. Acts as a costimulatory receptor for T-cell receptor (TCR) in CD8(+) T-cell-mediated adaptive immune responses by amplifying T-cell activation. Stimulates perforin-mediated elimination of ligand-expressing tumor cells. Signaling involves calcium influx, culminating in the expression of TNF-alpha. Participates in NK cell-mediated bone marrow graft rejection. May play a regulatory role in differentiation and survival of NK cells. Binds to ligands belonging to various subfamilies of MHC class I-related glycoproteins including MICA, MICB, RAET1E, RAET1G, RAET1L/ULBP6, ULBP1, ULBP2, ULBP3 (ULBP2>ULBP1>ULBP3) and ULBP4.
• Tissue Specificity: Expressed in natural killer (NK) cells, CD8(+) alpha-beta and gamma-delta T-cells. Expressed on essentially all CD56+CD3- NK cells from freshly isolated PBMC. Expressed in interferon-producing killer dendritic cells (IKDCs).
• KEGG Pathway:
  .tural killer cell mediated cytotoxicity (hsa04650)
  Malaria (hsa05144)
• Reactome Pathway:
  DAP12 interactions (R-HSA-2172127)
  DAP12 signaling (R-HSA-2424491)
  Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	NKG2-D type II integral membrane protein (KLRK1) increases the response to substance of Arsenic trioxide.	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of NKG2-D type II integral membrane protein (KLRK1).	[1]
Marinol	DM70IK5	Approved	Marinol increases the expression of NKG2-D type II integral membrane protein (KLRK1).	[2]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of NKG2-D type II integral membrane protein (KLRK1).	[3]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of NKG2-D type II integral membrane protein (KLRK1).	[4]

2 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 NKG2-D type II integral membrane protein (KLRK1).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of NKG2-D type II integral membrane protein (KLRK1).	[6]

References

• [1] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [2] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [3] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [4] Resveratrol enhances perforin expression and NK cell cytotoxicity through NKG2D-dependent pathways. J Cell Physiol. 2010 May;223(2):343-51. doi: 10.1002/jcp.22043.
• [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] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [7] Induction of NKG2D ligands and subsequent enhancement of NK cell-mediated lysis of cancer cells by arsenic trioxide. J Immunother. 2008 Jun;31(5):475-86. doi: 10.1097/CJI.0b013e3181755deb.