Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKMZ6QH)

• DOT Name: Toll-like receptor 6 (TLR6)
• Synonyms: CD antigen CD286
• Gene Name: TLR6
• UniProt ID: TLR6_HUMAN
• PDB ID: 4OM7
• Pfam ID: PF13855 ; PF01463 ; PF01582
• Sequence:
  MTKDKEPIVKSFHFVCLMIIIVGTRIQFSDGNEFAVDKSKRGLIHVPKDLPLKTKVLDMS
  QNYIAELQVSDMSFLSELTVLRLSHNRIQLLDLSVFKFNQDLEYLDLSHNQLQKISCHPI
  VSFRHLDLSFNDFKALPICKEFGNLSQLNFLGLSAMKLQKLDLLPIAHLHLSYILLDLRN
  YYIKENETESLQILNAKTLHLVFHPTSLFAIQVNISVNTLGCLQLTNIKLNDDNCQVFIK
  FLSELTRGSTLLNFTLNHIETTWKCLVRVFQFLWPKPVEYLNIYNLTIIESIREEDFTYS
  KTTLKALTIEHITNQVFLFSQTALYTVFSEMNIMMLTISDTPFIHMLCPHAPSTFKFLNF
  TQNVFTDSIFEKCSTLVKLETLILQKNGLKDLFKVGLMTKDMPSLEILDVSWNSLESGRH
  KENCTWVESIVVLNLSSNMLTDSVFRCLPPRIKVLDLHSNKIKSVPKQVVKLEALQELNV
  AFNSLTDLPGCGSFSSLSVLIIDHNSVSHPSADFFQSCQKMRSIKAGDNPFQCTCELREF
  VKNIDQVSSEVLEGWPDSYKCDYPESYRGSPLKDFHMSELSCNITLLIVTIGATMLVLAV
  TVTSLCIYLDLPWYLRMVCQWTQTRRRARNIPLEELQRNLQFHAFISYSEHDSAWVKSEL
  VPYLEKEDIQICLHERNFVPGKSIVENIINCIEKSYKSIFVLSPNFVQSEWCHYELYFAH
  HNLFHEGSNNLILILLEPIPQNSIPNKYHKLKALMTQRTYLQWPKEKSKRGLFWANIRAA
  FNMKLTLVTENNDVKS
• Function: Participates in the innate immune response to Gram-positive bacteria and fungi. Specifically recognizes diacylated and, to a lesser extent, triacylated lipopeptides. In response to diacylated lipopeptides, forms the activation cluster TLR2:TLR6:CD14:CD36, this cluster triggers signaling from the cell surface and subsequently is targeted to the Golgi in a lipid-raft dependent pathway. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Recognizes mycoplasmal macrophage-activating lipopeptide-2kD (MALP-2), soluble tuberculosis factor (STF), phenol-soluble modulin (PSM) and B.burgdorferi outer surface protein A lipoprotein (OspA-L) cooperatively with TLR2. In complex with TLR4, promotes sterile inflammation in monocytes/macrophages in response to oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42. In this context, the initial signal is provided by oxLDL- or amyloid-beta 42-binding to CD36. This event induces the formation of a heterodimer of TLR4 and TLR6, which is rapidly internalized and triggers inflammatory response, leading to the NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion.
• Tissue Specificity: Detected in monocytes, CD11c+ immature dendritic cells, plasmacytoid pre-dendritic cells and dermal microvessel endothelial cells.
• KEGG Pathway:
  Phagosome (hsa04145)
  Toll-like receptor sig.ling pathway (hsa04620)
  Salmonella infection (hsa05132)
  Chagas disease (hsa05142)
  Tuberculosis (hsa05152)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  MyD88 (R-HSA-166058)
  Toll Like Receptor TLR6 (R-HSA-168188)
  MyD88 deficiency (TLR2/4) (R-HSA-5602498)
  IRAK4 deficiency (TLR2/4) (R-HSA-5603041)
  Regulation of TLR by endogenous ligand (R-HSA-5686938)
  ER-Phagosome pathway (R-HSA-1236974)

Molecular Interaction Atlas (MIA) of This DOT

9 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 Toll-like receptor 6 (TLR6).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Toll-like receptor 6 (TLR6).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Toll-like receptor 6 (TLR6).	[3]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Toll-like receptor 6 (TLR6).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Toll-like receptor 6 (TLR6).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Toll-like receptor 6 (TLR6).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Toll-like receptor 6 (TLR6).	[7]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Toll-like receptor 6 (TLR6).	[8]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Toll-like receptor 6 (TLR6).	[9]

References

• [1] 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.
• [2] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [3] 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.
• [4] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [5] 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.
• [6] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [7] Cultured human peripheral blood mononuclear cells alter their gene expression when challenged with endocrine-disrupting chemicals. Toxicology. 2013 Jan 7;303:17-24.
• [8] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [9] Candida albicans and Saccharomyces cerevisiae induce interleukin-8 production from intestinal epithelial-like Caco-2 cells in the presence of butyric acid. FEMS Immunol Med Microbiol. 2004 Jul 1;41(3):227-35. doi: 10.1016/j.femsim.2004.03.006.