Ligand Binding and Functional Selectivity of l-Tryptophan Metabolites at the Mouse Aryl Hydrocarbon Receptor (mAhR)
Abstract
The aryl hydrocarbon receptor (AhR) is a nuclear receptor regulating a wide range of biological and toxicological effects. Metabolites of L-tryptophan are able to bind and activate AhR, providing a link between tryptophan catabolism and a novel mechanism of protective tolerance, referred to as "disease tolerance". The notion that pharmacologic modulation of genes associated with endotoxin tolerance would be beneficial in clinical settings dominated by acute hyperinflammatory responses to infection thrusts AhR into the limelight as an interesting druggable target. Combining homology modeling, docking studies, and molecular dynamic simulations with mutagenesis experiments and gene profiling, in this work we report that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and two different L-tryptophan metabolites, namely L-Kynurenine and FICZ (6-formylindolo[3,2-b]carbazole), are able to bind to mAhR, exploiting different key interactions with distinct set of fingerprint residues. As a result, they stabilize different conformations of mAhR that, in turn, selectively regulate downstream signaling and transcription of specific target genes. Collectively, these results open new avenues for the design and development of selective AhR modulators that, by targeting specific receptor conformations associated with specific AhR functions, may offer novel therapeutic opportunities in infectious diseases and other morbidity that may be associated with the receptor.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Employment of PAS-B structures of HIF-2α in complex with ligands as templates greatly improved the quality of the modeled binding site, and inclusion of receptor flexibility in docking enabled better description of the binding event.
“Not only did the employment of PAS-B structures of the homologous HIF-2α protein in complex with ligands as templates for modeling greatly improve the quality of the modeled binding site, but the inclusion of a certain degree of receptor flexibility in docking calculations enabled us and other investigators to better describe the binding event19,24–26.”
From Modeling the binding of diverse ligands within the Ah receptor ligand binding domain (2019) · cites this paper as [26]
Cites
AQUA and PROCHECK-NMR: Programs for checking the quality of protein structures solved by NMR
Laskowski, R., Rullmann, J. A., MacArthur, M., Kaptein, R., & Thornton, J. (1996) · Journal of Biomolecular NMR · doi:10.1007/bf00228148 · Cited by 5,502 · see citing works
VERIFY3D: assessment of protein models with three-dimensional profiles.
Eisenberg, D., Lüthy, R., & Bowie, J. (1997) · Methods in Enzymology · doi:10.1016/s0076-6879(97)77022-8 · Cited by 2,149 · see citing works
An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor
Opitz, C. A., Litzenburger, U. M., Sahm, F., Ott, M., Tritschler, I., Trump, S., Schumacher, T., Jestaedt, L., Schrenk, D., Weller, M., et al. (2011) · Nature · doi:10.1038/nature10491 · Cited by 1,898 · see citing works
Bochevarov, A. D., Harder, E. D., Hughes, T. F., Greenwood, J. R., Braden, D. A., Philipp, D. M., Rinaldo, D., Halls, M. D., Zhang, J., & Friesner, R. A. (2013) · International Journal of Quantum Chemistry · doi:10.1002/qua.24481 · Cited by 1,821 · see citing works
Identifying and Characterizing Binding Sites and Assessing Druggability
Halgren, T. A. (2009) · Journal of Chemical Information and Modeling · doi:10.1021/ci800324m · Cited by 1,771 · see citing works
An Interaction between Kynurenine and the Aryl Hydrocarbon Receptor Can Generate Regulatory T Cells
Mezrich, J. D., Fechner, J. H., Zhang, X., Johnson, B. P., Burlingham, W. J., & Bradfield, C. A. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0903670 · Cited by 1,617 · see citing works
Kr�utler, V., A, W. F. V. G., & Hünenberger, P. H. (2001) · Journal of Computational Chemistry · doi:10.1002/1096-987x(20010415)22:5 · Cited by 1,444 · see citing works
Functional Selectivity and Classical Concepts of Quantitative Pharmacology
Urban, J. D., Clarke, W. P., von Zastrow, M., Nichols, D. E., Kobilka, B. K., Weinstein, H., Javitch, J. A., Roth, B. L., Christopoulos, A., Sexton, P. M., et al. (2006) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.106.104463 · Cited by 1,119 · see citing works
MOLPROBITY: structure validation and all-atom contact analysis for nucleic acids and their complexes
Davis, I., Murray, L. W., Richardson, J. S., & Richardson, D. C. (2004) · Nucleic Acids Research · doi:10.1093/nar/gkh398 · Cited by 1,032 · see citing works
Protein Dynamism and Evolvability
Tokuriki, N., & Tawfik, D. S. (2009) · Science · doi:10.1126/science.1169375 · Cited by 932 · see citing works
AH RECEPTOR SIGNALING PATHWAYS
Schmidt, J. V., & Bradfield, C. A. (1996) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.12.1.55 · Cited by 899 · see citing works
Endogenous kynurenines as targets for drug discovery and development
Stone, T. W., & Darlington, L. G. (2002) · Nature Reviews Drug Discovery · doi:10.1038/nrd870 · Cited by 768 · 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
Aryl hydrocarbon receptor control of a disease tolerance defence pathway
Bessede, A., Gargaro, M., Pallotta, M. T., Matino, D., Servillo, G., Brunacci, C., Bicciato, S., Mazza, E. M. C., Macchiarulo, A., Vacca, C., et al. (2014) · Nature · doi:10.1038/nature13323 · Cited by 676 · see citing works
Self-citationThe mammalian basic helix–loop–helix/PAS family of transcriptional regulators
Kewley, R. J., Whitelaw, M. L., & Chapman‐Smith, A. (2003) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/s1357-2725(03)00211-5 · Cited by 590 · see citing works
Ligand binding and activation of the Ah receptor
Denison, M. S., Pandini, A., Nagy, S. R., Baldwin, E. P., & Bonati, L. (2002) · Chemico-Biological Interactions · doi:10.1016/s0009-2797(02)00063-7 · Cited by 485 · see citing works
Homology modeling in drug discovery: current trends and applications
Cavasotto, C. N., & Phatak, S. S. (2009) · Drug Discovery Today · doi:10.1016/j.drudis.2009.04.006 · Cited by 484 · see citing works
Matikainen, T., Perez, G. I., Jurisicova, A., Pru, J. K., Schlezinger, J. J., Ryu, H., Laine, J. T., Sakai, T., Korsmeyer, S. J., Casper, R. F., et al. (2001) · Nature Genetics · doi:10.1038/ng575 · Cited by 465 · see citing works
Cho, A. E., Guallar, V., Berne, B. J., & Friesner, R. A. (2005) · Journal of Computational Chemistry · doi:10.1002/jcc.20222 · Cited by 413 · see citing works
Rannug, A., Rannug, U., Rosenkranz, H. S., Winqvist, L., Westerholm, R. N., Agurell, E., & Grafström, A.-K. (1987) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)47743-5 · Cited by 357 · see citing works
CH223191 Is a Ligand-Selective Antagonist of the Ah (Dioxin) Receptor
Zhao, B., DeGroot, D. E., Hayashi, A., He, G., & Denison, M. S. (2010) · Toxicological Sciences · doi:10.1093/toxsci/kfq217 · Cited by 312 · see citing works
Artificial ligand binding within the HIF2α PAS-B domain of the HIF2 transcription factor
Scheuermann, T. H., Tomchick, D. R., Machius, M., Guo, Y., Bruick, R. K., & Gardner, K. H. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0808092106 · Cited by 301 · see citing works
An introduction to the molecular basics of aryl hydrocarbon receptor biology
Abel, J., & Haarmann‐Stemmann, T. (2010) · Biological Chemistry · doi:10.1515/bc.2010.128 · Cited by 297 · see citing works
Recent developments in biased agonism
Wisler, J. W., Xiao, K., Thomsen, A. R. B., & Lefkowitz, R. J. (2013) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2013.10.008 · Cited by 288 · 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
Gouédard, C., Barouki, R., & Morel, Y. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.12.5209-5222.2004 · Cited by 238 · see citing works
Endogenous and Exogenous Ligands of Aryl Hydrocarbon Receptor: Current State of Art
Stejskalová, L., Dvořák, Z., & Pávek, P. (2011) · Current Drug Metabolism · doi:10.2174/138920011795016818 · Cited by 231 · see citing works
Erbel, P. J. A., Card, P. B., Karakuzu, O., Bruick, R. K., & Gardner, K. H. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2533374100 · Cited by 227 · see citing works
Structure elucidation of two tryptophan-derived, high affinity Ah receptor ligands
Rannug, U., Rannug, A., Sjöberg, U., Li, H., Westerholm, R. N., & Bergman, J. (1995) · Chemistry & Biology · doi:10.1016/1074-5521(95)90090-x · Cited by 213 · see citing works
Pandini, A., Denison, M. S., Song, Y., Soshilov, A. A., & Bonati, L. (2007) · Biochemistry · doi:10.1021/bi061460t · Cited by 160 · see citing works
Bisson, W. H., Koch, D. C., O’Donnell, E. F., Khalil, S. M., Kerkvliet, N. I., Tanguay, R. L., Abagyan, R., & Kolluri, S. K. (2009) · Journal of Medicinal Chemistry · doi:10.1021/jm900199u · Cited by 149 · see citing works
The AhR twist: ligand-dependent AhR signaling and pharmaco-toxicological implications
Guyot, E., Chevallier, A., Barouki, R., & Coumoul, X. (2012) · Drug Discovery Today · doi:10.1016/j.drudis.2012.11.014 · Cited by 143 · see citing works
Card, P. B., Erbel, P. J. A., & Gardner, K. H. (2005) · Journal of Molecular Biology · doi:10.1016/j.jmb.2005.08.043 · Cited by 139 · see citing works
Connor, C. E., Norris, J. D., Broadwater, G., Willson, T. M., Gottardis, M. M., Dewhirst, M. W., & McDonnell, D. P. (2001) · PubMed · Cited by 131 · see citing works
Macchiarulo, A., Camaioni, E., Nuti, R., & Pellicciari, R. (2008) · Amino Acids · doi:10.1007/s00726-008-0137-3 · Cited by 129 · see citing works
Self-citationSelective Glucocorticoid Receptor modulators
Bosscher, K. D. (2010) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2010.02.027 · Cited by 129 · see citing works
Soshilov, A. A., & Denison, M. S. (2014) · Molecular and Cellular Biology · doi:10.1128/mcb.01183-13 · 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
Principles of ligand binding within a completely buried cavity in HIF2α PAS-B
Key, J., Scheuermann, T. H., Anderson, P., Daggett, V., & Gardner, K. (2009) · Journal of the American Chemical Society · doi:10.1021/ja9073062 · Cited by 119 · see citing works
DuSell, C. D., Nelson, E. R., Wang, X., Abdo, J., Mödder, U. I., Umetani, M., Gesty‐Palmer, D., Javitt, N. B., Khosla, S., & McDonnell, D. P. (2010) · Endocrinology · doi:10.1210/en.2010-0080 · Cited by 106 · see citing works
Safe, S. H., & McDougal, A. J. (2002) · International Journal of Oncology · doi:10.3892/ijo.20.6.1123 · Cited by 102 · 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
Lees, M. J., & Whitelaw, M. L. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.8.5811 · Cited by 95 · see citing works
AHR2 Mutant Reveals Functional Diversity of Aryl Hydrocarbon Receptors in Zebrafish
Goodale, B. C., La Du, J. K., Bisson, W. H., Janszen, D. B., Waters, K. M., & Tanguay, R. L. (2012) · PLoS ONE · doi:10.1371/journal.pone.0029346 · Cited by 89 · 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
Razeto, A., Ramakrishnan, V., Litterst, C. M., Giller, K., Griesinger, C., Carlomagno, T., Lakomek, N., Heimburg, T., Lodrini, M., Pfitzner, E., et al. (2004) · Journal of Molecular Biology · doi:10.1016/j.jmb.2003.12.057 · Cited by 77 · see citing works
Kazmin, D., Prytkova, T., Cook, C., Wolfinger, R., Chu, T.-M., Beratan, D., Norris, J., Chang, C.-Y., & McDonnell, D. (2006) · Molecular Endocrinology · doi:10.1210/me.2005-0309 · Cited by 72 · see citing works
Wheeler, J. L. H., Martin, K. C., Resseguie, E. A., & Lawrence, B. P. (2013) · Toxicological Sciences · doi:10.1093/toxsci/kft255 · Cited by 64 · see citing works
Soshilov, A., & Denison, M. S. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.246439 · Cited by 49 · see citing works
Henry, E. C., & Gasiewicz, T. A. (2003) · Molecular Pharmacology · doi:10.1124/mol.63.2.392 · Cited by 48 · see citing works
Cao, F., Li, X., Li, Y., Xie, Y., Wang, X., Shi, W. F., Qian, X., Zhu, Y., & Yu, H. (2013) · Environmental Toxicology and Pharmacology · doi:10.1016/j.etap.2013.06.004 · Cited by 27 · see citing works
Jogalekar, A. S., Reiling, S., & Vaz, R. J. (2010) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2010.09.019 · Cited by 23 · see citing works
Salzano, M., Marabotti, A., Milanesi, L., & Facchiano, A. M. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.08.039 · Cited by 19 · see citing works
Homodimerization of the PAS-B Domains of Hypoxia-Inducible Factors
Zhu, J., Martinez‐Yamout, M. A., Cardoso, R., Yan, J., Love, R. A., Grodsky, N. B., Brooun, A., & Dyson, H. J. (2012) · The Journal of Physical Chemistry B · doi:10.1021/jp300525n · Cited by 6 · see citing works
Computational and structural analysis of deleterious functional SNPs in ARNT oncogene
Doss, C. G. P., & Sethumadhavan, R. (2009) · Interdisciplinary Sciences Computational Life Sciences · doi:10.1007/s12539-009-0042-9 · Cited by 5 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Kynurenine pathway metabolism and the microbiota-gut-brain axis
Kennedy, P. J., Cryan, J. F., Dinan, T. G., & Clarke, G. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.07.002 · Cited by 724 · 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 · see citing works
Bonati, L., Corrada, D., Giani Tagliabue, S., & Motta, S. (2017) · Current Opinion in Toxicology · doi:10.1016/j.cotox.2017.01.011 · Cited by 27 · see citing works
- Authors
- Nuti, R., Gargaro, M., Matino, D., Dolciami, D., Grohmann, U., Puccetti, P., Fallarino, F., & Macchiarulo, A.
- Affiliations
- University of Perugia (IT)
- Corresponding author
- Macchiarulo, Antonio
- ORCID
- Venue
- Journal of Chemical Information and Modeling
- Publisher
- American Chemical Society (ACS)
- Published
- 2014-11-21
- Volume
- 54
- Issue
- 12
- Pages
- 3373-3383
- ISSN
- 1549-9596 (ISSN-L)
- 1549-960X
- OpenAlex
- W2054076776
- Cited by
- 45
- References
- 55
- Citations by year
- 2025: 2 · 2024: 4 · 2023: 5 · 2022: 1 · 2021: 6 · 2020: 2 · 2019: 8 · 2018: 3 · 2017: 6 · 2016: 7 · 2015: 1
- FWCI
- 4.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Chemical Information and Modeling (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Associazione Italiana per la Ricerca sul Cancro
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- aryl hydrocarbon receptor, kynurenine, FICZ, 2,3,7,8-tetrachlorodibenzo-p-dioxin, ligand binding, functional selectivity, disease tolerance, endotoxin tolerance, receptor conformation, transcriptional regulation, infectious diseases
- MeSH terms
- Polychlorinated Dibenzodioxins, Animals, Carbazoles, Kynurenine, Ligands, Protein Binding, Substrate Specificity, Tryptophan, Mutagenesis, Protein Structure, Tertiary, Receptors, Aryl Hydrocarbon, Mice, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors, Molecular Dynamics Simulation, Transcriptome, Molecular Docking Simulation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
