Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT61JMYX)

• DOT Name: C-C chemokine receptor type 6 (CCR6)
• Synonyms: C-C CKR-6; CC-CKR-6; CCR-6; Chemokine receptor-like 3; CKR-L3; DRY6; G-protein coupled receptor 29; GPR-CY4; GPRCY4; LARC receptor; CD antigen CD196
• Gene Name: CCR6
• UniProt ID: CCR6_HUMAN
• PDB ID: 6WWZ
• Pfam ID: PF00001
• Sequence:
  MSGESMNFSDVFDSSEDYFVSVNTSYYSVDSEMLLCSLQEVRQFSRLFVPIAYSLICVFG
  LLGNILVVITFAFYKKARSMTDVYLLNMAIADILFVLTLPFWAVSHATGAWVFSNATCKL
  LKGIYAINFNCGMLLLTCISMDRYIAIVQATKSFRLRSRTLPRSKIICLVVWGLSVIISS
  STFVFNQKYNTQGSDVCEPKYQTVSEPIRWKLLMLGLELLFGFFIPLMFMIFCYTFIVKT
  LVQAQNSKRHKAIRVIIAVVLVFLACQIPHNMVLLVTAANLGKMNRSCQSEKLIGYTKTV
  TEVLAFLHCCLNPVLYAFIGQKFRNYFLKILKDLWCVRRKYKSSGFSCAGRYSENISRQT
  SETADNDNASSFTM
• Function: Receptor for the C-C type chemokine CCL20. Binds to CCL20 and subsequently transduces a signal by increasing the intracellular calcium ion levels. Although CCL20 is its major ligand it can also act as a receptor for non-chemokine ligands such as beta-defensins. Binds to defensin DEFB1 leading to increase in intracellular calcium ions and cAMP levels. Its binding to DEFB1 is essential for the function of DEFB1 in regulating sperm motility and bactericidal activity. Binds to defensins DEFB4 and DEFB4A/B and mediates their chemotactic effects. The ligand-receptor pair CCL20-CCR6 is responsible for the chemotaxis of dendritic cells (DC), effector/ memory T-cells and B-cells and plays an important role at skin and mucosal surfaces under homeostatic and inflammatory conditions, as well as in pathology, including cancer and various autoimmune diseases. CCR6-mediated signals are essential for immune responses to microbes in the intestinal mucosa and in the modulation of inflammatory responses initiated by tissue insult and trauma. CCR6 is essential for the recruitment of both the pro-inflammatory IL17 producing helper T-cells (Th17) and the regulatory T-cells (Treg) to sites of inflammation. Required for the normal migration of Th17 cells in Peyers-patches and other related tissue sites of the intestine and plays a role in regulating effector T-cell balance and distribution in inflamed intestine. Plays an important role in the coordination of early thymocyte precursor migration events important for normal subsequent thymocyte precursor development, but is not required for the formation of normal thymic natural regulatory T-cells (nTregs). Required for optimal differentiation of DN2 and DN3 thymocyte precursors. Essential for B-cell localization in the subepithelial dome of Peyers-patches and for efficient B-cell isotype switching to IgA in the Peyers-patches. Essential for appropriate anatomical distribution of memory B-cells in the spleen and for the secondary recall response of memory B-cells. Positively regulates sperm motility and chemotaxis via its binding to CCL20.
• Tissue Specificity: Sperm. Mainly localized in the tail and in the postacrosomal region but is also found in the midpiece and basal region in a small percentage of sperm cells. Reduced levels found in the sperms of asthenozoospermia and leukocytospermia patients (at protein level). Spleen, lymph nodes, appendix, and fetal liver. Expressed in lymphocytes, T-cells and B-cells but not in natural killer cells, monocytes or granulocytes.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
  Chemokine sig.ling pathway (hsa04062)
• Reactome Pathway:
  Chemokine receptors bind chemokines (R-HSA-380108)
  G alpha (i) signalling events (R-HSA-418594)
  Beta defensins (R-HSA-1461957)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of C-C chemokine receptor type 6 (CCR6).	[1]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of C-C chemokine receptor type 6 (CCR6).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of C-C chemokine receptor type 6 (CCR6).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of C-C chemokine receptor type 6 (CCR6).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of C-C chemokine receptor type 6 (CCR6).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of C-C chemokine receptor type 6 (CCR6).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of C-C chemokine receptor type 6 (CCR6).	[6]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of C-C chemokine receptor type 6 (CCR6).	[7]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of C-C chemokine receptor type 6 (CCR6).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of C-C chemokine receptor type 6 (CCR6).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of C-C chemokine receptor type 6 (CCR6).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of C-C chemokine receptor type 6 (CCR6).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of C-C chemokine receptor type 6 (CCR6).	[11]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of C-C chemokine receptor type 6 (CCR6).	[13]
Paraoxon	DMN4ZKC	Investigative	Paraoxon increases the expression of C-C chemokine receptor type 6 (CCR6).	[14]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Differential expression of dendritic cell markers by all-trans retinoic acid on human acute promyelocytic leukemic cell line. Int Immunopharmacol. 2004 Dec 15;4(13):1587-601. doi: 10.1016/j.intimp.2004.07.010.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] Prenatal arsenic exposure and shifts in the newborn proteome: interindividual differences in tumor necrosis factor (TNF)-responsive signaling. Toxicol Sci. 2014 Jun;139(2):328-37. doi: 10.1093/toxsci/kfu053. Epub 2014 Mar 27.
• [6] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [7] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [8] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Inhibition of Super-Enhancer Activity in Autoinflammatory Site-Derived T Cells Reduces Disease-Associated Gene Expression. Cell Rep. 2015 Sep 29;12(12):1986-96. doi: 10.1016/j.celrep.2015.08.046. Epub 2015 Sep 17.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [13] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [14] Genomic and phenotypic alterations of the neuronal-like cells derived from human embryonal carcinoma stem cells (NT2) caused by exposure to organophosphorus compounds paraoxon and mipafox. Int J Mol Sci. 2014 Jan 9;15(1):905-26. doi: 10.3390/ijms15010905.