Ligand Promiscuity of Aryl Hydrocarbon Receptor Agonists and Antagonists Revealed by Site-Directed Mutagenesis

REFERENCES

• DeGroot DE, He G, Fraccalvieri D, Bonati L, Pandini A, Denison MS. 2011. AhR ligands: promiscuity in binding and diversity in response, p 63–79. In Pohjanvirta R (ed), The AH receptor in biology and toxicology. Wiley, Hoboken, NJ.
   Google Scholar
• Denison MS, Soshilov AA, He G, DeGroot DE, Zhao B. 2011. Exactly the same but different: promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor. Toxicol. Sci. 124:1–22. http://dx.doi.org/10.1093/toxsci/kfr218.
   PubMed Web of Science ®Google Scholar
• NTP. 2011. 12th report on carcinogens. Department of Health, Human Services, National Toxicology Program, Research Triangle Park, NC.
   Google Scholar
• White SS, Birnbaum LS. 2009. An overview of the effects of dioxins and dioxin-like compounds on vertebrates, as documented in human and ecological epidemiology. J. Environ. Sci. Health C Environ. Carcinog. Ecotoxicol. Rev. 27:197–211. http://dx.doi.org/10.1080/10590500903310047.
   PubMed Web of Science ®Google Scholar
• Berghard A, Gradin K, Toftgård R. 1992. The stability of dioxin-receptor ligands influences cytochrome P450IA1 expression in human keratinocytes. Carcinogenesis 13:651–655. http://dx.doi.org/10.1093/carcin/13.4.651.
   PubMedGoogle Scholar
• Kim MJ, Pelloux V, Guyot E, Tordjman J, Bui LC, Chevallier A, Forest C, Benelli C, Clement K, Barouki R. 2012. Inflammatory pathway genes belong to major targets of persistent organic pollutants in adipose cells. Environ. Health Perspect. 120:508–514. http://dx.doi.org/10.1289/ehp.1104282.
   PubMed Web of Science ®Google Scholar
• Riddick DS, Huang Y, Harper PA, Okey AB. 1994. 2,3,7,8-Tetrachlorodibenzo-p-dioxin versus 3-methylcholanthrene: comparative studies of Ah receptor binding, transformation, and induction of CYP1A1. J. Biol. Chem. 269:12118–12128.
   PubMed Web of Science ®Google Scholar
• Coumailleau P, Poellinger L, Gustafsson JA, Whitelaw ML. 1995. Definition of a minimal domain of the dioxin receptor that is associated with Hsp90 and maintains wild type ligand binding affinity and specificity. J. Biol. Chem. 270:25291–25300. http://dx.doi.org/10.1074/jbc.270.42.25291.
   PubMed Web of Science ®Google Scholar
• Fukunaga BN, Probst MR, Reisz-Porszasz S, Hankinson O. 1995. Identification of functional domains of the aryl hydrocarbon receptor. J. Biol. Chem. 270:29270–29278. http://dx.doi.org/10.1074/jbc.270.49.29270.
   PubMed Web of Science ®Google Scholar
• Soshilov A, Denison MS. 2011. Ligand displaces heat shock protein 90 from overlapping binding sites within the aryl hydrocarbon receptor ligand-binding domain. J. Biol. Chem. 286:35275–35282. http://dx.doi.org/10.1074/jbc.M111.246439.
   PubMed Web of Science ®Google Scholar
• Chen HS, Singh SS, Perdew GH. 1997. The Ah receptor is a sensitive target of geldanamycin-induced protein turnover. Arch. Biochem. Biophys. 348:190–198. http://dx.doi.org/10.1006/abbi.1997.0398.
   PubMed Web of Science ®Google Scholar
• Henry EC, Gasiewicz TA. 1993. Transformation of the aryl hydrocarbon receptor to a DNA-binding form is accompanied by release of the 90 kDa heat-shock protein and increased affinity for 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biochem. J. 294(Part 1):95–101.
   PubMedGoogle Scholar
• Pongratz I, Mason GG, Poellinger L. 1992. Dual roles of the 90-kDa heat shock protein hsp90 in modulating functional activities of the dioxin receptor. Evidence that the dioxin receptor functionally belongs to a subclass of nuclear receptors which require hsp90 both for ligand binding activity and repression of intrinsic DNA binding activity. J. Biol. Chem. 267:13728–13734.
   PubMed Web of Science ®Google Scholar
• Probst MR, Reisz-Porszasz S, Agbunag RV, Ong MS, Hankinson O. 1993. Role of the aryl hydrocarbon receptor nuclear translocator protein in aryl hydrocarbon (dioxin) receptor action. Mol. Pharmacol. 44:511–518.
   PubMed Web of Science ®Google Scholar
• Denison MS, Phelps CL, Dehoog J, Kim HJ, Bank PA, Yao EF. 1991. Species variation in Ah receptor transformation and DNA binding, p 337–349. In Gallo MA, Scheuplein RJ, Van Der, Heijden KA (ed), Banbury report no. 35: biological basis of risk assessment of dioxins and related compounds. Cold Spring Harbor Press, Cold Spring Harbor, NY.
   Google Scholar
• Denison MS, Fisher JM, Whitlock JPJr. 1988. The DNA recognition site for the dioxin-Ah receptor complex. Nucleotide sequence and functional analysis. J. Biol. Chem. 263:17221–17224.
   PubMed Web of Science ®Google Scholar
• Bunger MK, Glover E, Moran SM, Walisser JA, Lahvis GP, Hsu EL, Bradfield CA. 2008. Abnormal liver development and resistance to 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity in mice carrying a mutation in the DNA-binding domain of the aryl hydrocarbon receptor. Toxicol. Sci. 106:83–92. http://dx.doi.org/10.1093/toxsci/kfn149.
   PubMed Web of Science ®Google Scholar
• Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E, Caccamo M, Oukka M, Weiner HL. 2008. Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 453:65–71. http://dx.doi.org/10.1038/nature06880.
   PubMed Web of Science ®Google Scholar
• Boitano AE, Wang J, Romeo R, Bouchez LC, Parker AE, Sutton SE, Walker JR, Flaveny CA, Perdew GH, Denison MS, Schultz PG, Cooke MP. 2010. Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science 329:1345–1348. http://dx.doi.org/10.1126/science.1191536.
   PubMed Web of Science ®Google Scholar
• Gramatzki D, Pantazis G, Schittenhelm J, Tabatabai G, Kohle C, Wick W, Schwarz M, Weller M, Tritschler I. 2009. Aryl hydrocarbon receptor inhibition downregulates the TGF-beta/Smad pathway in human glioblastoma cells. Oncogene 28:2593–2605. http://dx.doi.org/10.1038/onc.2009.104.
   PubMed Web of Science ®Google Scholar
• Goodale BC, Tilton SC, Corvi MM, Wilson GR, Janszen DB, Anderson KA, Waters KM, Tanguay RL. 2013. Structurally distinct polycyclic aromatic hydrocarbons induce differential transcriptional responses in developing zebrafish. Toxicol. Appl. Pharmacol. 272:656–670. http://dx.doi.org/10.1016/j.taap.2013.04.024.
   PubMedGoogle Scholar
• Hrubá E, Vondráček J, Líbalová H, Topinka J, Bryja V, Souček K, Machala M. 2011. Gene expression changes in human prostate carcinoma cells exposed to genotoxic and nongenotoxic aryl hydrocarbon receptor ligands. Toxicol. Lett. 206:178–188. http://dx.doi.org/10.1016/j.toxlet.2011.07.011.
   PubMedGoogle Scholar
• Ovando BJ, Ellison CA, Vezina CM, Olson JR. 2010. Toxicogenomic analysis of exposure to TCDD, PCB126, and PCB153: identification of genomic biomarkers of exposure to AhR ligands. BMC Genomics 11:583. http://dx.doi.org/10.1186/1471-2164-11-583.
   PubMedGoogle Scholar
• Gouedard C, Barouki R, Morel Y. 2004. Dietary polyphenols increase paraoxonase 1 gene expression by an aryl hydrocarbon receptor-dependent mechanism. Mol. Cell. Biol. 24:5209–5222. http://dx.doi.org/10.1128/MCB.24.12.5209-5222.2004.
   PubMed Web of Science ®Google Scholar
• Matikainen T, Perez GI, Jurisicova A, Pru JK, Schlezinger JJ, Ryu HY, Laine J, Sakai T, Korsmeyer SJ, Casper RF, Sherr DH, Tilly JL. 2001. Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals. Nat. Genet. 28:355–360. http://dx.doi.org/10.1038/ng575.
   PubMed Web of Science ®Google Scholar
• Murray IA, Morales JL, Flaveny CA, DiNatale BC, Chiaro C, Gowdahalli K, Amin S, Perdew GH. 2010. Evidence for ligand-mediated selective modulation of aryl hydrocarbon receptor activity. Mol. Pharmacol. 77:247–254. http://dx.doi.org/10.1124/mol.109.061788.
   PubMed Web of Science ®Google Scholar
• Zhang S, Rowlands C, Safe S. 2008. Ligand-dependent interactions of the Ah receptor with coactivators in a mammalian two-hybrid assay. Toxicol. Appl. Pharmacol. 227:196–206. http://dx.doi.org/10.1016/j.taap.2007.10.019.
   PubMed Web of Science ®Google Scholar
• Ngan C-H, Beglov D, Rudnitskaya AN, Kozakov D, Waxman DJ, Vajda S. 2009. The structural basis of pregnane X receptor binding promiscuity. Biochemistry 48:11572–11581. http://dx.doi.org/10.1021/bi901578n.
   PubMed Web of Science ®Google Scholar
• Ekins S, Chang C, Mani S, Krasowski MD, Reschly EJ, Iyer M, Kholodovych V, Ai N, Welsh WJ, Sinz M, Swaan PW, Patel R, Bachmann K. 2007. Human pregnane X receptor antagonists and agonists define molecular requirements for different binding sites. Mol. Pharmacol. 72:592–603. http://dx.doi.org/10.1124/mol.107.038398.
   PubMed Web of Science ®Google Scholar
• Mani S, Dou W, Redinbo MR. 2013. PXR antagonists and implication in drug metabolism. Drug Metab. Rev. 45:60–72. http://dx.doi.org/10.3109/03602532.2012.746363.
   PubMed Web of Science ®Google Scholar
• Zhao B, Degroot DE, Hayashi A, He G, Denison MS. 2010. CH223191 is a ligand-selective antagonist of the Ah (Dioxin) receptor. Toxicol. Sci. 117:393–403. http://dx.doi.org/10.1093/toxsci/kfq217.
   PubMed Web of Science ®Google Scholar
• Motto I, Bordogna A, Soshilov AA, Denison MS, Bonati L. 2011. New aryl hydrocarbon receptor homology model targeted to improve docking reliability. J. Chem. Inf. Model. 51:2868–2881. http://dx.doi.org/10.1021/ci2001617.
   PubMed Web of Science ®Google Scholar
• Pandini A, Soshilov AA, Song Y, Zhao J, Bonati L, Denison MS. 2009. Detection of the TCDD binding-fingerprint within the Ah receptor ligand binding domain by structurally driven mutagenesis and functional analysis. Biochemistry 48:5972–5983. http://dx.doi.org/10.1021/bi900259z.
   PubMed Web of Science ®Google Scholar
• Backlund M, Ingelman-Sundberg M. 2004. Different structural requirements of the ligand binding domain of the aryl hydrocarbon receptor for high- and low-affinity ligand binding and receptor activation. Mol. Pharmacol. 65:416–425. http://dx.doi.org/10.1124/mol.65.2.416.
   PubMed Web of Science ®Google Scholar
• Goryo K, Suzuki A, Carpio CAD, Siizaki K, Kuriyama E, Mikami Y, Kinoshita K, Yasumoto K-I, Rannug A, Miyamoto A, Fujii-Kuriyama Y, Sogawa K. 2007. Identification of amino acid residues in the Ah receptor involved in ligand binding. Biochem. Biophys. Res. Commun. 354:396–402. http://dx.doi.org/10.1016/j.bbrc.2006.12.227.
   PubMedGoogle Scholar
• Whelan F, Hao N, Furness SGB, Whitelaw ML, Chapman-Smith A. 2010. Amino acid substitutions in the aryl hydrocarbon receptor ligand binding domain reveal YH439 as an atypical AhR activator. Mol. Pharmacol. 77:1037–1046. http://dx.doi.org/10.1124/mol.109.062927.
   PubMed Web of Science ®Google Scholar
• Poland A, Palen D, Glover E. 1994. Analysis of the four alleles of the murine aryl hydrocarbon receptor. Mol. Pharmacol. 46:915–921.
   PubMed Web of Science ®Google Scholar
• Fukunaga BN, Hankinson O. 1996. Identification of a novel domain in the aryl hydrocarbon receptor required for DNA binding. J. Biol. Chem. 271:3743–3749. http://dx.doi.org/10.1074/jbc.271.7.3743.
   PubMed Web of Science ®Google Scholar
• Soshilov A, Denison MS. 2008. Role of the Per/Arnt/Sim domains in ligand-dependent transformation of the aryl hydrocarbon receptor. J. Biol. Chem. 283:32995–33005. http://dx.doi.org/10.1074/jbc.M802414200.
   PubMed Web of Science ®Google Scholar
• Karchner SI, Franks DG, Kennedy SW, Hahn ME. 2006. The molecular basis for differential dioxin sensitivity in birds: role of the aryl hydrocarbon receptor. Proc. Natl. Acad. Sci. U. S. A. 103:6252–6257. http://dx.doi.org/10.1073/pnas.0509950103.
   PubMedGoogle Scholar
• Rushing SR, Denison MS. 2002. The silencing mediator of retinoic acid and thyroid hormone receptors can interact with the aryl hydrocarbon (Ah) receptor but fails to repress Ah receptor-dependent gene expression. Arch. Biochem. Biophys. 403:189–201. http://dx.doi.org/10.1016/S0003-9861(02)00233-3.
   PubMed Web of Science ®Google Scholar
• Wincent E, Bengtsson J, Mohammadi Bardbori A, Alsberg T, Luecke S, Rannug U, Rannug A. 2012. Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor. Proc. Natl. Acad. Sci. U. S. A. 109:4479–4484. http://dx.doi.org/10.1073/pnas.1118467109.
   PubMed Web of Science ®Google Scholar
• Rannug U, Rannug A, Sjoberg U, Li H, Westerholm R, Bergman J. 1995. Structure elucidation of two tryptophan-derived, high affinity Ah receptor ligands. Chem. Biol. 2:841–845.
   PubMed Web of Science ®Google Scholar
• Scheuermann TH, Tomchick DR, Machius M, Guo Y, Bruick RK, Gardner KH. 2009. Artificial ligand binding within the HIF2alpha PAS-B domain of the HIF2 transcription factor. Proc. Natl. Acad. Sci. U. S. A. 106:450–455. http://dx.doi.org/10.1073/pnas.0808092106.
   PubMed Web of Science ®Google Scholar
• Goodale BC, La Du JK, Bisson WH, Janszen DB, Waters KM, Tanguay RL. 2012. Ahr2 mutant reveals functional diversity of aryl hydrocarbon receptors in zebrafish. PLoS One 7:e29346. http://dx.doi.org/10.1371/journal.pone.0029346.
   PubMedGoogle Scholar
• O'Donnell EF, Saili KS, Koch DC, Kopparapu PR, Farrer D, Bisson WH, Mathew LK, Sengupta S, Kerkvliet NI, Tanguay RL, Kolluri SK. 2010. The anti-inflammatory drug leflunomide is an agonist of the aryl hydrocarbon receptor. PLoS One 5:e13128. http://dx.doi.org/10.1371/journal.pone.0013128.
   PubMed Web of Science ®Google Scholar
• Blank JA, Tucker AN, Sweatlock J, Gasiewicz TA, Luster MI. 1987. Alpha-naphthoflavone antagonism of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced murine lymphocyte ethoxyresorufin-O-deethylase activity and immunosuppression. Mol. Pharmacol. 32:169–172.
   PubMedGoogle Scholar
• Santostefano M, Merchant M, Arellano L, Morrison V, Denison MS, Safe S. 1993. Alpha-naphthoflavone-induced CYP1A1 gene expression and cytosolic aryl hydrocarbon receptor transformation. Mol. Pharmacol. 43:200–206.
   PubMed Web of Science ®Google Scholar
• Lu YF, Santostefano M, Cunningham BD, Threadgill MD, Safe S. 1995. Identification of 3′-methoxy-4′-nitroflavone as a pure aryl hydrocarbon (Ah) receptor antagonist and evidence for more than one form of the nuclear Ah receptor in MCF-7 human breast cancer cells. Arch. Biochem. Biophys. 316:470–477. http://dx.doi.org/10.1006/abbi.1995.1062.
   PubMed Web of Science ®Google Scholar
• Zhou J, Gasiewicz TA. 2003. 3′-Methoxy-4′-nitroflavone, a reported aryl hydrocarbon receptor antagonist, enhances Cyp1a1 transcription by a dioxin responsive element-dependent mechanism. Arch. Biochem. Biophys. 416:68–80. http://dx.doi.org/10.1016/S0003-9861(03)00274-1.
   PubMedGoogle Scholar
• Perdew GH. 1988. Association of the Ah receptor with the 90-kDa heat shock protein. J. Biol. Chem. 263:13802–13805.
   PubMed Web of Science ®Google Scholar
• Antonsson C, Whitelaw ML, McGuire J, Gustafsson JA, Poellinger L. 1995. Distinct roles of the molecular chaperone hsp90 in modulating dioxin receptor function via the basic helix-loop-helix and PAS domains. Mol. Cell. Biol. 15:756–765.
   PubMed Web of Science ®Google Scholar
• Gouedard C, Barouki R, Morel Y. 2004. Induction of the paraoxonase-1 gene expression by resveratrol. Arterioscler. Thromb Vasc. Biol. 24:2378–2383. http://dx.doi.org/10.1161/01.ATV.0000146530.24736.ce.
   PubMed Web of Science ®Google Scholar
• Murray IA, Flaveny CA, Chiaro CR, Sharma AK, Tanos RS, Schroeder JC, Amin SG, Bisson WH, Kolluri SK, Perdew GH. 2011. Suppression of cytokine-mediated complement factor gene expression through selective activation of the Ah receptor with 3′,4′-dimethoxy-alpha-naphthoflavone. Mol. Pharmacol. 79:508–519. http://dx.doi.org/10.1124/mol.110.069369.
   PubMed Web of Science ®Google Scholar
• Murray IA, Krishnegowda G, DiNatale BC, Flaveny C, Chiaro C, Lin JM, Sharma AK, Amin S, Perdew GH. 2010. Development of a selective modulator of aryl hydrocarbon (Ah) receptor activity that exhibits anti-inflammatory properties. Chem. Res. Toxicol. 23:955–966. http://dx.doi.org/10.1021/tx100045h.
   PubMed Web of Science ®Google Scholar
• Chen I, McDougal A, Wang F, Safe S. 1998. Aryl hydrocarbon receptor-mediated antiestrogenic and antitumorigenic activity of diindolylmethane. Carcinogenesis 19:1631–1639. http://dx.doi.org/10.1093/carcin/19.9.1631.
   PubMed Web of Science ®Google Scholar
• McDougal A, Wilson C, Safe S. 1997. Inhibition of 7,12-dimethylbenz[a]anthracene-induced rat mammary tumor growth by aryl hydrocarbon receptor agonists. Cancer Lett. 120:53–63. http://dx.doi.org/10.1016/S0304-3835(97)00299-1.
   PubMed Web of Science ®Google Scholar
• Huang G, Elferink CJ. 2012. A novel nonconsensus xenobiotic response element capable of mediating aryl hydrocarbon receptor-dependent gene expression. Mol. Pharmacol. 81:338–347. http://dx.doi.org/10.1124/mol.111.075952.
   PubMedGoogle Scholar
• Petkov PI, Rowlands JC, Budinsky R, Zhao B, Denison MS, Mekenyan O. 2010. Mechanism-based common reactivity pattern (COREPA) modelling of aryl hydrocarbon receptor binding affinity. SAR QSAR Environ. Res. 21:187–214. http://dx.doi.org/10.1080/10629360903570933.
   PubMed Web of Science ®Google Scholar
• Fraccalvieri D, Soshilov AA, Karchner SI, Franks DG, Pandini A, Bonati L, Hahn ME, Denison MS. 2013. Comparative analysis of homology models of the Ah receptor ligand binding domain: verification of structure-function predictions by site-directed mutagenesis of a nonfunctional receptor. Biochemistry 52:714–725. http://dx.doi.org/10.1021/bi301457f.
   PubMedGoogle Scholar
• Eisenberg D, McLachlan AD. 1986. Solvation energy in protein folding and binding. Nature 319:199–203. http://dx.doi.org/10.1038/319199a0.
   PubMed Web of Science ®Google Scholar
• Flaveny CA, Perdew GH. 2009. Transgenic humanized AhR mouse reveals differences between human and mouse AhR ligand selectivity. Mol. Cell. Pharmacol. 1:119–123. http://dx.doi.org/10.4255/mcpharmacol.09.15.
   PubMedGoogle Scholar
• Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M, Jugold M, Guillemin GJ, Miller CL, Lutz C, Radlwimmer B, Lehmann I, von Deimling A, Wick W, Platten M. 2011. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478:197–203. http://dx.doi.org/10.1038/nature10491.
   PubMed Web of Science ®Google Scholar
• Henry EC, Bemis JC, Henry O, Kende AS, Gasiewicz TA. 2006. A potential endogenous ligand for the aryl hydrocarbon receptor has potent agonist activity in vitro and in vivo. Arch. Biochem. Biophys. 450:67–77. http://dx.doi.org/10.1016/j.abb.2006.02.008.
   PubMed Web of Science ®Google Scholar
• Savouret J-F, Antenos M, Quesne M, Xu J, Milgrom E, Casper RF. 2001. 7-Ketocholesterol is an endogenous modulator for the arylhydrocarbon receptor. J. Biol. Chem. 276:3054–3059. http://dx.doi.org/10.1074/jbc.M005988200.
   PubMed Web of Science ®Google Scholar
• Phelan D, Winter GM, Rogers WJ, Lam JC, Denison MS. 1998. Activation of the Ah receptor signal transduction pathway by bilirubin and biliverdin. Arch. Biochem. Biophys. 357:155–163. http://dx.doi.org/10.1006/abbi.1998.0814.
   PubMed Web of Science ®Google Scholar