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Aryl hydrocarbon receptor

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2951

Nomenclature: Aryl hydrocarbon receptor

Family: Aryl hydrocarbon receptor

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 848 7p21.1 AHR aryl hydrocarbon receptor
Mouse - 848 12 15.78 cM Ahr aryl-hydrocarbon receptor
Rat - 853 6q16 Ahr aryl hydrocarbon receptor
Database Links Click here for help
Alphafold P35869 (Hs), P30561 (Mm), P41738 (Rn)
ChEMBL Target CHEMBL3201 (Hs), CHEMBL6099 (Mm), CHEMBL5400 (Rn)
Ensembl Gene ENSG00000106546 (Hs), ENSMUSG00000019256 (Mm), ENSRNOG00000004342 (Rn)
Entrez Gene 196 (Hs), 11622 (Mm), 25690 (Rn)
Human Protein Atlas ENSG00000106546 (Hs)
KEGG Gene hsa:196 (Hs), mmu:11622 (Mm), rno:25690 (Rn)
OMIM 600253 (Hs)
Pharos P35869 (Hs)
RefSeq Nucleotide NM_001621 (Hs), NM_001314027 (Mm), NM_001308254 (Rn)
RefSeq Protein NP_001612 (Hs), NP_001300956 (Mm), NP_001295183 (Rn)
UniProtKB P35869 (Hs), P30561 (Mm), P41738 (Rn)
Wikipedia AHR (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the AHR-ARNT heterodimer in complex with the DRE
PDB Id:  5V0L
Resolution:  4.0Å
Species:  Human
References:  10

Download all structure-activity data for this target as a CSV file go icon to follow link

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
indolo[3,2-b]carbazole Small molecule or natural product Mm Agonist 9.7 pKd 1
⤷ pKd 9.7 (Kd 1.9x10-10 M) [1]
Description: Radioligand displacement binding of [2-1251]7,8-dibromodibenzo-pdioxin to AhR prepared from C57BL/6J mouse liver cytosol.
tapinarof Small molecule or natural product Approved drug Primary target of this compound Immunopharmacology Ligand Hs Agonist 6.7 – 7.0 pKd 13
⤷ pKd 6.7 – 7.0 (Kd 2x10-7 – 1x10-7 M) [13]
Description: Direct binding of tapinarof to the AhR-ARNT heterodimer by fluorescence assay.
indole-3-carbinol Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Mm Agonist 4.6 pKd 1
⤷ pKd 4.6 (Kd 2.7x10-5 M) [1]
Description: Radioligand displacement binding of [2-1251]7,8-dibromodibenzo-pdioxin to AhR prepared from C57BL/6J mouse liver cytosol.
TCDD Small molecule or natural product Hs Agonist - -
⤷
View species-specific agonist tables
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
ezutromid Small molecule or natural product Hs Antagonist 7.3 pKd 15
⤷ pKd 7.3 (Kd 5x10-8 M) [15]
Description: apparent binding affinity determined using affinity‐based protein profiling (AfBPP), in a cellular context.
Immunopharmacology Comments
The AhR is activated by small signalling molecules derived from the diet, microorganisms and environmental agents, and when expressed by immune cells, it integrates the effects of the environment and metabolism on the immune response [9]. The AhR is a critical regulator of innate and adaptive immune responses that influences the balance of Th17 and Treg cells [2,7]. A role in environmentally-induced fibrosis is reported [11]. AhR is widely expressed in the skin where it is important for the development and maintenance of the skin barrier [12], and is also implicated in lung epithelial barrier immune surveillance [6,14]. AhR agonists are now being exploited for immunomodulatory potential, particulary for anti-inflammatory activity [3] in skin diseases like psoriasis and atopic dermatitis (see tapinarof for example [13]) [4,8,16]. The role of the AhR in modulating the immune response in health and disease is reviewed by Gutiérrez-Vázquez and Quintana (2018) [5].
Immuno Process Associations
Immuno Process:  B cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Cellular signalling
Immuno Process:  Immune system development
General Comments
The AhR is a cytosolic ligand-activated transcription factor. It senses a wide range of endogenous and exogenous molecules, recruiting downstream pathways that impact on a variety of biological processes.

References

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1. Bjeldanes LF, Kim JY, Grose KR, Bartholomew JC, Bradfield CA. (1991) Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Proc Natl Acad Sci USA, 88 (21): 9543-7. [PMID:1658785]

2. Bock KW. (2020) Aryl hydrocarbon receptor (AHR) functions: Balancing opposing processes including inflammatory reactions. Biochem Pharmacol, 178: 114093. [PMID:32535108]

3. Di Meglio P, Duarte JH, Ahlfors H, Owens ND, Li Y, Villanova F, Tosi I, Hirota K, Nestle FO, Mrowietz U et al.. (2014) Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions. Immunity, 40 (6): 989-1001. [PMID:24909886]

4. Gargaro M, Pirro M, Romani R, Zelante T, Fallarino F. (2016) Aryl Hydrocarbon Receptor-Dependent Pathways in Immune Regulation. Am J Transplant, 16 (8): 2270-6. [PMID:26751261]

5. Gutiérrez-Vázquez C, Quintana FJ. (2018) Regulation of the Immune Response by the Aryl Hydrocarbon Receptor. Immunity, 48 (1): 19-33. [PMID:29343438]

6. Lee SM, Park HY, Suh YS, Yoon EH, Kim J, Jang WH, Lee WS, Park SG, Choi IW, Choi I et al.. (2017) Inhibition of acute lethal pulmonary inflammation by the IDO-AhR pathway. Proc Natl Acad Sci USA, 114 (29): E5881-E5890. [PMID:28673995]

7. Mascanfroni ID, Takenaka MC, Yeste A, Patel B, Wu Y, Kenison JE, Siddiqui S, Basso AS, Otterbein LE, Pardoll DM et al.. (2015) Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-α. Nat Med, 21 (6): 638-46. [PMID:26005855]

8. Mulero-Navarro S, Fernandez-Salguero PM. (2016) New Trends in Aryl Hydrocarbon Receptor Biology. Front Cell Dev Biol, 4: 45. [PMID:27243009]

9. Rothhammer V, Quintana FJ. (2019) The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat Rev Immunol, 19 (3): 184-197. [PMID:30718831]

10. Seok SH, Lee W, Jiang L, Molugu K, Zheng A, Li Y, Park S, Bradfield CA, Xing Y. (2017) Structural hierarchy controlling dimerization and target DNA recognition in the AHR transcriptional complex. Proc Natl Acad Sci USA, 114 (21): 5431-5436. [PMID:28396409]

11. Shi Y, Zeng Z, Yu J, Tang B, Tang R, Xiao R. (2020) The aryl hydrocarbon receptor: An environmental effector in the pathogenesis of fibrosis. Pharmacol Res, 160: 105180. [PMID:32877693]

12. Smith KJ, Boyer JA, Muku GE, Murray IA, Gowda K, Desai D, Amin SG, Glick AB, Perdew GH. (2017) Editor's Highlight: Ah Receptor Activation Potentiates Neutrophil Chemoattractant (C-X-C Motif) Ligand 5 Expression in Keratinocytes and Skin. Toxicol Sci, 160 (1): 83-94. [PMID:28973351]

13. Smith SH, Jayawickreme C, Rickard DJ, Nicodeme E, Bui T, Simmons C, Coquery CM, Neil J, Pryor WM, Mayhew D et al.. (2017) Tapinarof Is a Natural AhR Agonist that Resolves Skin Inflammation in Mice and Humans. J Invest Dermatol, 137 (10): 2110-2119. [PMID:28595996]

14. Thatcher TH, Williams MA, Pollock SJ, McCarthy CE, Lacy SH, Phipps RP, Sime PJ. (2016) Endogenous ligands of the aryl hydrocarbon receptor regulate lung dendritic cell function. Immunology, 147 (1): 41-54. [PMID:26555456]

15. Wilkinson IVL, Perkins KJ, Dugdale H, Moir L, Vuorinen A, Chatzopoulou M, Squire SE, Monecke S, Lomow A, Geese M et al.. (2020) Chemical Proteomics and Phenotypic Profiling Identifies the Aryl Hydrocarbon Receptor as a Molecular Target of the Utrophin Modulator Ezutromid. Angew Chem Int Ed Engl, 59 (6): 2420-2428. [PMID:31755636]

16. Zhou L. (2016) AHR Function in Lymphocytes: Emerging Concepts. Trends Immunol, 37 (1): 17-31. [PMID:26700314]

How to cite this page

Aryl hydrocarbon receptor: Aryl hydrocarbon receptor. Last modified on 23/02/2021. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2951.