Transitional States in Ligand-Dependent Transformation of the Aryl Hydrocarbon Receptor into Its DNA-Binding Form
Open accessAbstract
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the biological and toxicological effects of an AhR lacking the entire PASB structurally diverse chemicals, including halogenated aromatic hydrocarbons. Ligand-dependent transformation of the AhR into its DNA binding form involves a ligand-dependent conformational change, heat shock protein 90 (hsp90), dissociation from the AhR complex and AhR dimerization with the AhR nuclear translocator (ARNT) protein. The mechanism of AhR transformation was examined using mutational approaches and stabilization of the AhR:hsp90 complex with sodium molybdate. Insertion of a single mutation (F281A) in the hsp90-binding region of the AhR resulted in its constitutive (ligand-independent) transformation/DNA binding in vitro. Mutations of AhR residues within the Arg-Cys-rich region (R212A, R217A, R219A) and Asp371 (D371A) impaired AhR transformation without a significant effect on ligand binding. Stabilization of AhR:hsp90 binding with sodium molybdate decreased transformation/DNA binding of the wild type AhR but had no effect on constitutively active AhR mutants. Interestingly, transformation of the AhR in the presence of molybdate allowed detection of an intermediate transformation ternary complex containing hsp90, AhR, and ARNT. These results are consistent with a stepwise transformation mechanism in which binding of ARNT to the liganded AhR:hsp90 complex results in a progressive displacement of hsp90 and conversion of the AhR into its high affinity DNA binding form. The available molecular insights into the signaling mechanism of other Per-ARNT-Sim (PAS) domains and structural information on hsp90 association with other client proteins are consistent with the proposed transformation mechanism of the AhR.
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A transitional state may exist where ARNT can directly engage with AHR while AHR is still bound to HSP90 and XAP2.
“suggesting the possible existence of a transitional state where ARNT can directly engage with AHR while it is still bound to HSP90 and XAP248.”
From Structural basis for the ligand-dependent activation of heterodimeric AHR-ARNT complex (2025) · cites this paper as [48]
The Discussion (page unavailable) proposes a transitional hsp90:AhR:ARNT complex in which ARNT binds AhR before hsp90 is fully released. It does not establish that XAP2 remains bound in that state, so the XAP2 portion of the claim is unsupported. (LLM, conf=0.87)
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Cites
Denison, M. S., & Nagy, S. R. (2003) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.43.100901.135828 · Cited by 1,895 · see citing works
Self-citationSchopf, F. H., Biebl, M. M., & Buchner, J. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.20 · Cited by 1,540 · see citing works
Rothhammer, V., & Quintana, F. J. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-019-0125-8 · Cited by 1,197 · see citing works
The aryl hydrocarbon receptor: multitasking in the immune system
Stockinger, B., Meglio, P. D., Gialitakis, M., & Duarte, J. H. (2014) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032713-120245 · Cited by 909 · see citing works
Fernández‐Salguero, P. M., Hilbert, D. M., Rudikoff, S., Ward, J. M., & Gonzalez, F. J. (1996) · Toxicology and Applied Pharmacology · doi:10.1006/taap.1996.0210 · Cited by 835 · see citing works
Denison, M. S., Soshilov, A. A., He, G., DeGroot, D. E., & Zhao, B. (2011) · Toxicological Sciences · doi:10.1093/toxsci/kfr218 · Cited by 748 · see citing works
Self-citationThe Search for Endogenous Activators of the Aryl Hydrocarbon Receptor
Nguyen, L. P., & Bradfield, C. A. (2007) · Chemical Research in Toxicology · doi:10.1021/tx7001965 · Cited by 705 · see citing works
Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation
Hubbard, T. D., Murray, I. A., & Perdew, G. H. (2015) · Drug Metabolism and Disposition · doi:10.1124/dmd.115.064246 · Cited by 646 · see citing works
Structure and Signaling Mechanism of Per-ARNT-Sim Domains
Möglich, A., Ayers, R. A., & Moffat, K. (2009) · Structure · doi:10.1016/j.str.2009.08.011 · Cited by 524 · see citing works
The Aryl Hydrocarbon Receptor in Barrier Organ Physiology, Immunology, and Toxicology
Esser, C., & Rannug, A. (2015) · Pharmacological Reviews · doi:10.1124/pr.114.009001 · Cited by 501 · see citing works
Denison, M. S., Fisher, J. M., & Whitlock, J. P. (1988) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)77819-3 · Cited by 451 · see citing works
Self-citationAtomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase
Verba, K. A., Wang, R. Y.-R., Arakawa, A., Liu, Y., Shirouzu, M., Yokoyama, S., & Agard, D. A. (2016) · Science · doi:10.1126/science.aaf5023 · Cited by 424 · see citing works
Structural integration in hypoxia-inducible factors
Wu, D., Potluri, N., Lu, J., Kim, Y., & Rastinejad, F. (2015) · Nature · doi:10.1038/nature14883 · Cited by 346 · see citing works
Identification of Functional Domains of the Aryl Hydrocarbon Receptor
Fukunaga, B. N., Probst, M. R., Reisz-Porszasz, S., & Hankinson, O. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.49.29270 · Cited by 338 · see citing works
The mechanism of dioxin toxicity: relationship to risk assessment.
Birnbaum, L. S. (1994) · Environmental Health Perspectives · doi:10.1289/ehp.94102s9157 · Cited by 336 · see citing works
Halavaty, A. S., & Moffat, K. (2007) · Biochemistry · doi:10.1021/bi701543e · Cited by 317 · see citing works
Analysis of the four alleles of the murine aryl hydrocarbon receptor
Poland, A., Palen, D., & Glover, E. (1994) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)09833-5 · Cited by 303 · see citing works
Nuclear Localization and Export Signals of the Human Aryl Hydrocarbon Receptor
Ikuta, T., Eguchi, H., Tachibana, T., Yoneda, Y., & Kawajiri, K. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.5.2895 · Cited by 287 · see citing works
Denison, M. S., Fisher, J. M., & Whitlock, J. P. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.8.2528 · Cited by 254 · see citing works
Self-citationIn vitro analysis of Ah receptor domains involved in ligand-activated DNA recognition.
Dolwick, K. M., Swanson, H. I., & Bradfield, C. A. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.18.8566 · Cited by 239 · see citing works
Probst, M. R., Reisz-Porszasz, S., Agbunag, R. V., Ong, M. S., & Hankinson, O. (1993) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)13218-5 · Cited by 214 · see citing works
Lindebro, M. C., Poellinger, L., & Whitelaw, M. L. (1995) · EMBO Journal · doi:10.1002/j.1460-2075.1995.tb07359.x · Cited by 209 · see citing works
Karchner, S. I., Franks, D. G., Kennedy, S. W., & Hahn, M. E. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0509950103 · Cited by 207 · see citing works
Binding of Aryl Hydrocarbon Receptor (AhR) to AhR-interacting Protein
Bell, D., & Poland, A. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m004236200 · Cited by 180 · see citing works
Whitelaw, M., Gustafsson, J.-Å., & Poellinger, L. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.12.8343-8355.1994 · Cited by 174 · see citing works
Coumailleau, P., Poellinger, L., Gustafsson, J.-Å., & Whitelaw, M. L. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.42.25291 · Cited by 172 · see citing works
Whitelaw, M. L., Gustafsson, J.-Α., & Poellinger, L. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.12.8343 · Cited by 161 · see citing works
Whitelaw, M., Göttlicher, M., Gustafsson, J.-Å., & Poellinger, L. (1993) · EMBO Journal · doi:10.1002/j.1460-2075.1993.tb06101.x · Cited by 157 · see citing works
The AH Receptor in Biology and Toxicology
Pohjanvirta, R. (2011) · Wiley eBooks · doi:10.1002/9781118140574 · Cited by 141 · see citing works
Bunger, M. K., Glover, E., Moran, S. M., Walisser, J. A., Lahvis, G. P., Hsu, E. L., & Bradfield, C. A. (2008) · Toxicological Sciences · doi:10.1093/toxsci/kfn149 · Cited by 139 · see citing works
A Ligand-Induced Switch in the Periplasmic Domain of Sensor Histidine Kinase CitA
Sevvana, M., Vijayan, V., Zweckstetter, M., Reinelt, S., Madden, D. R., Herbst‐Irmer, R., Sheldrick, G. M., Bott, M. H., Griesinger, C., & Becker, S. (2008) · Journal of Molecular Biology · doi:10.1016/j.jmb.2008.01.024 · Cited by 134 · see citing works
Denison, M. S., & Faber, S. C. (2017) · Current Opinion in Toxicology · doi:10.1016/j.cotox.2017.01.006 · Cited by 131 · see citing works
Self-citationDere, E., Lo, R., Celius, T., Matthews, J. B., & Zacharewski, T. R. (2011) · BMC Genomics · doi:10.1186/1471-2164-12-365 · Cited by 128 · see citing works
Pandini, A., Soshilov, A. A., Song, Y., Zhao, J., Bonati, L., & Denison, M. S. (2009) · Biochemistry · doi:10.1021/bi900259z · Cited by 124 · see citing works
Self-citationHeid, S. E., Pollenz, R. S., & Swanson, H. I. (2000) · Molecular Pharmacology · doi:10.1016/s0026-895x(24)26445-2 · Cited by 120 · see citing works
The activation mechanism of the aryl hydrocarbon receptor (AhR) by molecular chaperone HSP90
Tsuji, N., Fukuda, K., Nagata, Y., Okada, H., Haga, A., Hatakeyama, S., Yoshida, S., Okamoto, T., Hosaka, M., Sekine, K., et al. (2014) · FEBS Open Bio · doi:10.1016/j.fob.2014.09.003 · Cited by 117 · see citing works
Modeling the binding of diverse ligands within the Ah receptor ligand binding domain
Giani Tagliabue, S., Faber, S. C., Motta, S., Denison, M. S., & Bonati, L. (2019) · Scientific Reports · doi:10.1038/s41598-019-47138-z · Cited by 106 · cited 1× · see citing works
“Although the three-dimensional structure of the AhR PASB domain has been obtained by homology modeling [30], and both ligand binding [31] and dimerization with ARNT [32,33] have been computationally simulated, to date, the molecular effects of ligand binding on the mechanism of AhR transformation are not yet well unde…”
MethodSelf-citationEvidence for Ligand-Mediated Selective Modulation of Aryl Hydrocarbon Receptor Activity
Murray, I. A., Morales, J. L., Flaveny, C. A., DiNatale, B. C., Chiaro, C. R., Gowda, K., Amin, S., & Perdew, G. H. (2009) · Molecular Pharmacology · doi:10.1124/mol.109.061788 · Cited by 100 · see citing works
Role of the Per/Arnt/Sim Domains in Ligand-dependent Transformation of the Aryl Hydrocarbon Receptor
Soshilov, A., & Denison, M. S. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m802414200 · Cited by 99 · see citing works
Self-citationLees, M. J., & Whitelaw, M. L. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.8.5811 · Cited by 95 · see citing works
Identification of a Novel Domain in the Aryl Hydrocarbon Receptor Required for DNA Binding
Fukunaga, B. N., & Hankinson, O. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.7.3743 · Cited by 91 · see citing works
The aryl hydrocarbon receptor in the crossroad of signalling networks with therapeutic value
Román, Á., Carvajal-González, J. M., Merino, J. M., Mulero‐Navarro, S., & Fernández‐Salguero, P. M. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.12.003 · Cited by 86 · see citing works
New Aryl Hydrocarbon Receptor Homology Model Targeted To Improve Docking Reliability
Motto, I., Bordogna, A., Soshilov, A. A., Denison, M. S., & Bonati, L. (2011) · Journal of Chemical Information and Modeling · doi:10.1021/ci2001617 · Cited by 80 · see citing works
Self-citationThe Ah Receptor Is a Sensitive Target of Geldanamycin-Induced Protein Turnover
Chen, H.-S., Singh, S. S., & Perdew, G. H. (1997) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1997.0398 · Cited by 76 · see citing works
Crystal Structures of Deoxy and CO-Bound bjFixLH Reveal Details of Ligand Recognition and Signaling
Key, J., & Moffat, K. (2005) · Biochemistry · doi:10.1021/bi047942r · Cited by 75 · see citing works
Persistent Binding of Ligands to the Aryl Hydrocarbon Receptor
Bohonowych, J. E. S., & Denison, M. S. (2007) · Toxicological Sciences · doi:10.1093/toxsci/kfm085 · Cited by 75 · see citing works
Self-citationFraccalvieri, D., Soshilov, A. A., Karchner, S. I., Franks, D. G., Pandini, A., Bonati, L., Hahn, M. E., & Denison, M. S. (2013) · Biochemistry · doi:10.1021/bi301457f · Cited by 65 · cited 1× · see citing works
“Ligand binding to the AhR has been extensively studied, and the overall fingerprint amino acid residues (those presumably in contact with the bound ligand), as well as the amino acid residues implicated in differences in AhR affinity among many species, have been characterized [30,39,40,43,44].”
BackgroundSelf-citationMapping the 90 kDa heat shock protein binding region of the Ah receptor
Perdew, G. H., & Bradfield, C. A. (1996) · IUBMB Life · doi:10.1080/15216549600201651 · Cited by 63 · cited 7× · see citing works
“Ligand-dependent displacement of hsp90 from the PASB could be an initial and sufficient structural change that triggers AhR transformation through changes in conformation and interactions of the AhR:hsp90 complex and/or within AhR domains [16,21,24,43].”
BackgroundMethodInfluentialSun, W., Zhang, J., & Hankinson, O. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.50.31845 · Cited by 63 · see citing works
The regulation mechanisms of AhR by molecular chaperone complex
Kudo, I., Hosaka, M., Haga, A., Tsuji, N., Nagata, Y., Okada, H., Fukuda, K., Kakizaki, Y., Okamoto, T., Grave, E., et al. (2018) · The Journal of Biochemistry · doi:10.1093/jb/mvx074 · Cited by 63 · see citing works
Henry, E. C., & Gasiewicz, T. A. (1993) · Biochemical Journal · doi:10.1042/bj2940095 · Cited by 60 · see citing works
Analysis of the Aryl Hydrocarbon Receptor (<scp>Ah</scp><scp>R</scp>) Signal Transduction Pathway
Denison, M. S., Rogers, J. M., Rushing, S. R., Jones, C. L., Tetangco, S. C., & Heath‐Pagliuso, S. (2002) · Current Protocols in Toxicology · doi:10.1002/0471140856.tx0408s11 · Cited by 55 · see citing works
Self-citationHepatic Ah receptor for 2,3,7,8-tetrachlorodibenzo-p-dioxin. Partial stabilization by molybdate.
Denison, M. S., Vella, L. M., & Okey, A. B. (1986) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)67509-x · Cited by 53 · see citing works
Self-citationSoshilov, A., & Denison, M. S. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.246439 · Cited by 49 · cited 8× · see citing works
“While ligand binding may directly contribute to the destabilization of hsp90 bound within the AhR PASB (Per-ARNT-Sim B) ligand binding domain (LBD), located C-terminal to the PASA domain, it does not fully displace hsp90 from the AhR [16,21,23].”
BackgroundMethodResultInfluentialSelf-citationCorrada, D., Soshilov, A. A., Denison, M. S., & Bonati, L. (2016) · PLOS Computational Biology · doi:10.1371/journal.pcbi.1004981 · Cited by 43 · see citing works
Self-citationPerdew, G. H. (1991) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(91)90136-7 · Cited by 38 · see citing works
In vitro transformation of the human Ah receptor and its binding to a dioxin response element.
Harper, P. A., Giannone, J. V., Okey, A. B., & Denison, M. S. (1992) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)08989-8 · Cited by 36 · see citing works
Self-citationNault, R., Karmaus, A. L., Dere, E., & Zacharewski, T. R. (2013) · Toxicology Letters · doi:10.1016/j.toxlet.2013.08.013 · Cited by 31 · see citing works
Corrada, D., Denison, M. S., & Bonati, L. (2017) · Molecular BioSystems · doi:10.1039/c7mb00005g · Cited by 24 · see citing works
Self-citationLigand-induced perturbation of the HIF-2α:ARNT dimer dynamics
Motta, S., Minici, C., Corrada, D., Bonati, L., & Pandini, A. (2018) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1006021 · Cited by 24 · see citing works
Self-citationInhibitors of Molecular Chaperones as Therapeutic Agents
(2013) · Royal Society of Chemistry eBooks · doi:10.1039/9781849739689 · Cited by 22 · see citing works
Blankenburg, L., Schroeder, L. A., Habenstein, F., et al. (2019) · Physical Chemistry Chemical Physics · doi:10.1039/c8cp05399e · Cited by 18 · see citing works
Soshilov, A. A., & Denison, M. S. (2013) · Methods in pharmacology and toxicology · doi:10.1007/978-1-62703-742-6_12 · Cited by 14 · see citing works
Self-citationOverview of Molecular Chaperones in Health and Disease
Wang, T., Echeverría, P. C., & Picard, D. (2013) · Royal Society of Chemistry eBooks · doi:10.1039/9781849739689-00001 · Cited by 5 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [34]Denison M.S. Phelps C.L. Dehoog J. Kim H.J. Bank P.A. Yao E.F. Species Variation in Ah Receptor Transformation and DNA Binding Banbury Report 35: Biological Basis for Risk Assessment of Dioxins and Related Compounds Gallo M.A. Scheuplein R.J. van der Heihjden K.A. Cold Spring Harbor Laboratory Press Cold Spring Harbor, NY, USA 1991 337 349
Cited by
Sorted by citations
Cryo-EM structure of the agonist-bound Hsp90-XAP2-AHR cytosolic complex
Gruszczyk, J., Grandvuillemin, L., Lai-Kee-Him, J., Paloni, M., Savva, C. G., Germain, P., Grimaldi, M., Boulahtouf, A., Kwong, H.-S., Bous, J., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34773-w · Cited by 137 · see citing works
Grishanova, A. Y., & Perepechaeva, M. L. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23126719 · Cited by 130 · see citing works
Structural basis for the ligand-dependent activation of heterodimeric AHR-ARNT complex
Diao, X., Shang, Q., Guo, M., Huang, Y., Zhang, M., Chen, X., Liang, Y., Sun, X., Zhou, F., Zhuang, J., et al. (2025) · Nature communications · doi:10.1038/s41467-025-56574-7 · Cited by 72 · see citing works
“Interestingly, we observed that the spatial location of the ARNT PAS-B domain does not directly con fl ict with HSP90 or XAP2, suggesting the possible existence of a transitional state where ARNT can directly engage with AHR while it is still bound to HSP90 and XAP2 48 .”
Cryo-EM structure of the cytosolic AhR complex.
Wen, Z., Zhang, Y., Zhang, B., Hang, Y., Xu, L., Chen, Y., Xie, Q., Zhao, Q., Zhang, L., Li, G., et al. (2023) · Structure · doi:10.1016/j.str.2022.12.013 · Cited by 51 · see citing works
- Authors
- Soshilov, A. A., Motta, S., Bonati, L., & Denison, M. S.
- Affiliations
- University of California, Davis (US)
- University of Milano-Bicocca (IT)
- Corresponding author
- Denison, Michael S.
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2020-04-02
- Volume
- 21
- Issue
- 7
- Pages
- 2474
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC7177239
- OpenAlex
- W3014759680
- Cited by
- 36
- References
- 64
- Citations by year
- 2026: 1 · 2025: 8 · 2024: 7 · 2023: 8 · 2022: 5 · 2021: 5 · 2020: 2
- FWCI
- 2.00
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- BOA (University of Milano-Bicocca) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (R01-ES007685)
- Topics
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- aryl hydrocarbon receptor, HSP90, ARNT, PAS domain, conformational change, sodium molybdate, constitutively active mutant, ternary complex, halogenated aromatic hydrocarbons, transcription factor activation, heat shock proteins
- MeSH terms
- Amino Acid Sequence, Cell Transformation, Neoplastic, DNA, DNA-Binding Proteins, Humans, Ligands, Models, Molecular, Molybdenum, Mutation, Protein Binding, Structure-Activity Relationship, Receptors, Aryl Hydrocarbon, HSP90 Heat-Shock Proteins, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Protein Interaction Domains and Motifs
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