Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT904HBN)

• DOT Name: Cysteinyl leukotriene receptor 1 (CYSLTR1)
• Synonyms: CysLTR1; Cysteinyl leukotriene D4 receptor; LTD4 receptor; G-protein coupled receptor HG55; HMTMF81
• Gene Name: CYSLTR1
• UniProt ID: CLTR1_HUMAN
• PDB ID: 6RZ4; 6RZ5
• Pfam ID: PF00001
• Sequence:
  MDETGNLTVSSATCHDTIDDFRNQVYSTLYSMISVVGFFGNGFVLYVLIKTYHKKSAFQV
  YMINLAVADLLCVCTLPLRVVYYVHKGIWLFGDFLCRLSTYALYVNLYCSIFFMTAMSFF
  RCIAIVFPVQNINLVTQKKARFVCVGIWIFVILTSSPFLMAKPQKDEKNNTKCFEPPQDN
  QTKNHVLVLHYVSLFVGFIIPFVIIIVCYTMIILTLLKKSMKKNLSSHKKAIGMIMVVTA
  AFLVSFMPYHIQRTIHLHFLHNETKPCDSVLRMQKSVVITLSLAASNCCFDPLLYFFSGG
  NFRKRLSTFRKHSLSSVTYVPRKKASLPEKGEEICKV
• Function: Receptor for cysteinyl leukotrienes mediating bronchoconstriction of individuals with and without asthma. Stimulation by LTD4 results in the contraction and proliferation of smooth muscle, edema, eosinophil migration and damage to the mucus layer in the lung. This response is mediated via a G-protein that activates a phosphatidylinositol-calcium second messenger system. The rank order of affinities for the leukotrienes is LTD4 >> LTE4 = LTC4 >> LTB4.
• Tissue Specificity: Widely expressed, with highest levels in spleen and peripheral blood leukocytes. Lower expression in several tissues, such as lung (mostly in smooth muscle bundles and alveolar macrophages), placenta, small intestine, pancreas, colon and heart.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  LTC4-CYSLTR mediated IL4 production (R-HSA-9664535)
  Potential therapeutics for SARS (R-HSA-9679191)
  Leukotriene receptors (R-HSA-391906)

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
LTD4	DMIUZX3	Investigative	Cysteinyl leukotriene receptor 1 (CYSLTR1) increases the response to substance of LTD4.	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cysteinyl leukotriene receptor 1 (CYSLTR1).	[1]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Cysteinyl leukotriene receptor 1 (CYSLTR1).	[2]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Cysteinyl leukotriene receptor 1 (CYSLTR1).	[3]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Cysteinyl leukotriene receptor 1 (CYSLTR1).	[5]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of Cysteinyl leukotriene receptor 1 (CYSLTR1).	[2]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Cysteinyl leukotriene receptor 1 (CYSLTR1).	[6]

6 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Zafirlukast	DMHNQOG	Approved	Zafirlukast affects the binding of Cysteinyl leukotriene receptor 1 (CYSLTR1).	[4]
Pranlukast	DMYHDCA	Approved	Pranlukast affects the binding of Cysteinyl leukotriene receptor 1 (CYSLTR1).	[4]
LTC4	DM702WR	Investigative	LTC4 affects the binding of Cysteinyl leukotriene receptor 1 (CYSLTR1).	[4]
LTE4	DMCPB0Q	Investigative	LTE4 affects the binding of Cysteinyl leukotriene receptor 1 (CYSLTR1).	[7]
BAYu9773	DMXQ14V	Investigative	BAYu9773 affects the binding of Cysteinyl leukotriene receptor 1 (CYSLTR1).	[4]
CGP-57698	DMYZ72J	Investigative	CGP-57698 affects the binding of Cysteinyl leukotriene receptor 1 (CYSLTR1).	[4]

References

• [1] 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.
• [2] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [3] Differential contribution of the CysLTR1 gene in patients with aspirin hypersensitivity. J Clin Immunol. 2007 Nov;27(6):613-9. doi: 10.1007/s10875-007-9115-x. Epub 2007 Jul 20.
• [4] A kinetic binding study to evaluate the pharmacological profile of a specific leukotriene C(4) binding site not coupled to contraction in human lun... Mol Pharmacol. 2000 Jun;57(6):1182-9.
• [5] 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.
• [6] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [7] Characterization of the leukotriene D4 receptor in dimethylsulphoxide-differentiated U937 cells: comparison with the leukotriene D4 receptor in human lung and guinea-pig lung. Eur J Pharmacol. 1993 Feb 15;244(3):239-50. doi: 10.1016/0922-4106(93)90149-4.
• [8] Effects of the cysteinyl leukotriene receptor antagonists pranlukast and zafirlukast on tracheal mucus secretion in ovalbumin-sensitized guinea-pigs in vitro. Br J Pharmacol. 1998 Jun;124(3):563-71. doi: 10.1038/sj.bjp.0701886.