Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8ZYKJ6)

• DOT Name: Toll-like receptor 5 (TLR5)
• Synonyms: Toll/interleukin-1 receptor-like protein 3
• Gene Name: TLR5
• UniProt ID: TLR5_HUMAN
• PDB ID: 3J0A; 8AR2
• Pfam ID: PF00560 ; PF13855 ; PF01582
• Sequence:
  MGDHLDLLLGVVLMAGPVFGIPSCSFDGRIAFYRFCNLTQVPQVLNTTERLLLSFNYIRT
  VTASSFPFLEQLQLLELGSQYTPLTIDKEAFRNLPNLRILDLGSSKIYFLHPDAFQGLFH
  LFELRLYFCGLSDAVLKDGYFRNLKALTRLDLSKNQIRSLYLHPSFGKLNSLKSIDFSSN
  QIFLVCEHELEPLQGKTLSFFSLAANSLYSRVSVDWGKCMNPFRNMVLEILDVSGNGWTV
  DITGNFSNAISKSQAFSLILAHHIMGAGFGFHNIKDPDQNTFAGLARSSVRHLDLSHGFV
  FSLNSRVFETLKDLKVLNLAYNKINKIADEAFYGLDNLQVLNLSYNLLGELYSSNFYGLP
  KVAYIDLQKNHIAIIQDQTFKFLEKLQTLDLRDNALTTIHFIPSIPDIFLSGNKLVTLPK
  INLTANLIHLSENRLENLDILYFLLRVPHLQILILNQNRFSSCSGDQTPSENPSLEQLFL
  GENMLQLAWETELCWDVFEGLSHLQVLYLNHNYLNSLPPGVFSHLTALRGLSLNSNRLTV
  LSHNDLPANLEILDISRNQLLAPNPDVFVSLSVLDITHNKFICECELSTFINWLNHTNVT
  IAGPPADIYCVYPDSFSGVSLFSLSTEGCDEEEVLKSLKFSLFIVCTVTLTLFLMTILTV
  TKFRGFCFICYKTAQRLVFKDHPQGTEPDMYKYDAYLCFSSKDFTWVQNALLKHLDTQYS
  DQNRFNLCFEERDFVPGENRIANIQDAIWNSRKIVCLVSRHFLRDGWCLEAFSYAQGRCL
  SDLNSALIMVVVGSLSQYQLMKHQSIRGFVQKQQYLRWPEDLQDVGWFLHKLSQQILKKE
  KEKKKDNNIPLQTVATIS
• Function: Pattern recognition receptor (PRR) located on the cell surface that participates in the activation of innate immunity and inflammatory response. Recognizes small molecular motifs named pathogen-associated molecular pattern (PAMPs) expressed by pathogens and microbe-associated molecular patterns (MAMPs) usually expressed by resident microbiota. Upon ligand binding such as bacterial flagellins, recruits intracellular adapter proteins MYD88 and TRIF leading to NF-kappa-B activation, cytokine secretion and induction of the inflammatory response. Plays thereby an important role in the relationship between the intestinal epithelium and enteric microbes and contributes to the gut microbiota composition throughout life.
• Tissue Specificity: Highly expressed on the basolateral surface of intestinal epithelia . Expressed also in other cells such as lung epithelial cells .
• KEGG Pathway:
  Toll-like receptor sig.ling pathway (hsa04620)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Legionellosis (hsa05134)
  Inflammatory bowel disease (hsa05321)
• Reactome Pathway:
  MyD88 deficiency (TLR5) (R-HSA-5602680)
  IRAK4 deficiency (TLR5) (R-HSA-5603037)
  MyD88 cascade initiated on plasma membrane (R-HSA-975871)
  Toll Like Receptor 5 (TLR5) Cascade (R-HSA-168176)

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
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Toll-like receptor 5 (TLR5).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Toll-like receptor 5 (TLR5).	[2]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Toll-like receptor 5 (TLR5).	[3]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Toll-like receptor 5 (TLR5).	[4]
Aripiprazole	DM3NUMH	Approved	Aripiprazole increases the expression of Toll-like receptor 5 (TLR5).	[5]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Toll-like receptor 5 (TLR5).	[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 decreases the methylation of Toll-like receptor 5 (TLR5).	[6]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [4] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [5] Small Molecule Antipsychotic Aripiprazole Potentiates Ozone-Induced Inflammation in Airway Epithelium. Chem Res Toxicol. 2019 Oct 21;32(10):1997-2005. doi: 10.1021/acs.chemrestox.9b00149. Epub 2019 Sep 11.
• [6] 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.
• [7] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.