Detection of the TCDD Binding-Fingerprint within the Ah Receptor Ligand Binding Domain by Structurally Driven Mutagenesis and Functional Analysis
Open accessAbstract
The aryl hydrocarbon receptor (AhR) is a ligand-dependent, basic helix-loop-helix Per-Arnt-Sim (PAS)-containing transcription factor that can bind and be activated by structurally diverse chemicals, including the toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Our previous three-dimensional homology model of the mouse AhR (mAhR) PAS B ligand binding domain allowed identification of the binding site and its experimental validation. We have extended this analysis by conducting comparative structural modeling studies of the ligand binding domains of six additional high-affinity mammalian AhRs. These results, coupled with site-directed mutagenesis and AhR functional analysis, have allowed detection of the "TCDD binding-fingerprint" of conserved residues within the ligand binding cavity necessary for high-affinity TCDD binding and TCDD-dependent AhR transformation DNA binding. The essential role of selected residues was further evaluated using molecular docking simulations of TCDD with both wild-type and mutant mAhRs. Taken together, our results dramatically improve our understanding of the molecular determinants of TCDD binding and provide a basis for future studies directed toward rationalizing the observed species differences in AhR sensitivity to TCDD and understanding the mechanistic basis for the dramatic diversity in AhR ligand structure.
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Experimental confirmation of predicted binding modes for TCDD and other ligands in the AHR LBD is generally lacking.
“While the binding modes of TCDD and other ligands within the AHR LBD of a given species (typically that of mouse or human AHR) have been predicted by these approaches, experimental confirmation of these proposed interactions are generally lacking.”
From 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 (2013) · cites this paper as [18]
The Abstract and Discussion report experimental validation of predicted TCDD-binding residues through site-directed mutagenesis and functional analysis. The paper therefore provides experimental support for proposed TCDD interactions rather than saying such confirmation is lacking. It does not establish how often binding modes for other ligands have been confirmed. (LLM, conf=0.83)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe authors and others have used crystal and NMR structures of homologous protein domains to build homology models of the AHR LBD.
“While the lack of any three-dimensional structure information on the AHR ligand binding domain (LBD) has prevented detailed molecular analysis of the mechanisms of AHR ligand binding, we and others have used the availability of crystal and nuclear magnetic resonance (NMR) structures of homologous protein domains to develop homology models of the AHR LBD for such analysis (12,17-20).”
From 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 (2013) · cites this paper as [18]
The Materials and Methods section (Homology Modeling; page unavailable) says the authors used NMR structures of homologous HIF-2α and ARNT PAS B domains as templates for AhR LBD homology models. The paper also mentions earlier mouse AhR LBD models, but the passages found do not establish the claim's crystal-structure component. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn the model, a Val at position 375 creates steric hindrance at one end of the cavity, reducing cavity volume and potentially altering interactions with other fingerprint residues.
“When this amino acid is mutated to Val, it introduces steric hindrance at this end of the modeled cavity (Figure 2C), effectively decreasing the cavity volume and potentially affecting ligand interactions with other fingerprint residues (17,18).”
From 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 (2013) · cites this paper as [18]
The Discussion (page not available) describes increased steric hindrance at position 375 and reduced internal cavity space in modeled mutants; the Results on molecular docking also report weaker predicted TCDD binding for A375V. The paper describes position 375 as central, not at one end of the cavity, and these passages do not establish that Val alters ligand interactions with other fingerprint residues. (LLM, conf=0.82)
Experimental — accuracy not yet measuredHomology models have been used in molecular docking to study interactions of known agonists within the AHR LBD and in virtual screening of putative ligands.
“More recently, these models have been used in molecular docking studies in an attempt to elucidate the detailed interactions of some known ligands (agonists) within the AHR LBD as well as in the virtual screening of collections of putative ligands (12,18-20,22-25).”
From 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 (2013) · cites this paper as [18]
The Materials and Methods and Results sections on Molecular Docking describe using a homology model of the mouse AHR ligand-binding domain to dock TCDD and examine its binding interactions. Our copy does not report virtual screening of collections of putative ligands, so it supports the docking portion but not that portion of the claim. (LLM, conf=0.87)
Experimental — accuracy not yet measuredMD simulations allowed an improved description of the ligand binding modes and identification of all interacting residues.
“MD simulations allowed us to obtain an improved description of the ligand binding modes and the identification of all the interacting residues21,24,43.”
From Modeling the binding of diverse ligands within the Ah receptor ligand binding domain (2019) · cites this paper as [21]
The Results (Molecular Docking; page unavailable) describe a predicted TCDD binding position and report that residues implicated by mutagenesis lie close to the docked ligand. But the Methods (Molecular Docking; page unavailable) describe rigid-body docking, not MD simulations. The paper therefore supports analysis of a binding mode and contributing residues, but not the claim that MD simulations produced it or identified all interacting residues. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Homology models of the AHR ligand-binding domain exist for only a small number of species.
“homology models of the AHR ligand-binding domain (LBD) are available for only a few species.”
Homology models of the AHR LBD have revealed key structural features and, when combined with site-directed mutagenesis and functional assays, have helped identify amino acids important for ligand binding and ligand-dependent activation.
“These theoretical models not only have revealed key structural aspects of the domain, but when coupled with site directed mutagenesis and functional analysis, have proven to be helpful in identifying amino acids important in ligand binding and ligand-dependent AHR activation (12,17-19,21).”
The absence of three-dimensional structure information for the AHR LBD has prevented detailed molecular analysis of AHR ligand binding mechanisms.
“While the lack of any three-dimensional structure information on the AHR ligand binding domain (LBD) has prevented detailed molecular analysis of the mechanisms of AHR ligand binding, we and others have used the availability of crystal and nuclear magnetic resonance (NMR) structures of homologous protein domains to develop homology models of the AHR LBD for such analysis (12,17-20).”
Both substitutions involve residues inside the modeled cavities and belong to the mammalian TCDD-binding fingerprint.
“Both these substitutions involve residues that are internal to the modeled cavities and that belong to the “TCDD-binding fingerprint” for mammalian AHRs (18).”
Hydrophobic stabilization by the long Ile319 side chain (position 324/325 in ch/tAHR) was previously proposed as necessary for optimal TCDD binding by mAHR.
“Accordingly, hydrophobic stabilization by the long Ile319 side chain (corresponding to position 324/325 in the ch/tAHR) has been previously suggested to be necessary for optimal TCDD binding by mAHR (18).”
A consensus cavity for high-affinity mammalian AHRs was previously defined as the cavity bounded by internal residues conserved across all modeled LBDs.
“For the mammalian AHRs with relatively high affinity for TCDD (first seven AHRs in Table 1) a “consensus cavity” was previously defined as the cavity delimited by the internal residues (obtained by CASTp) that are conserved in all the modeled LBDs (18).”
Seven internal residues form the TCDD-binding fingerprint in high-affinity mammalian AHRs, identified by mutagenesis and functional analysis as necessary for optimal TCDD binding.
“In high affinity mammalian AHRs, seven internal residues have been shown to constitute the “TCDD-binding fingerprint” (i.e. the residues identified by site-directed mutagenesis and functional analysis of the mAHR LBD as necessary for optimal TCDD binding (18; Figure 2B and 2C).”
Per-residue decomposition of ΔGbind for the best pose identified a set of residues that stabilize all the ligands, most belonging to the previously published TCDD-binding fingerprint.
“By analyzing the different profiles obtained by per-residue decomposition of the ΔGbind for the best pose (the one with the lowest ΔGbind, Table S5) for each of the ligands under study (Fig. 5a) it was possible to identify a set of residues that stabilize all the ligands, with most of them belonging to the previously published “TCDD-binding fingerprint”21.”
From Modeling the binding of diverse ligands within the Ah receptor ligand binding domain (2019) · cites this paper as [21]
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“address species selective differences in TCDD binding [6,17] and to identify potential binding patterns of agonists and antagonists of the AHR [6,13,18,19].”
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Self-citationBonati, 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
Self-citationJogalekar, 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
Whelan, F., Hao, N., Furness, S. G. B., Whitelaw, M. L., & Chapman-Smith, A. (2010) · Molecular Pharmacology · doi:10.1124/mol.109.062927 · Cited by 22 · see citing works
In vitro toxicity and in silico docking analysis of two novel selective AH-receptor modulators
Mahiout, S., Tagliabue, S. G., Nasri, A., Omoruyi, I. M., Pettersson, L., Bonati, L., & Pohjanvirta, R. (2018) · Toxicology in Vitro · doi:10.1016/j.tiv.2018.06.010 · Cited by 19 · see citing works
Self-citation
- Authors
- Pandini, A., Soshilov, A. A., Song, Y., Zhao, J., Bonati, L., & Denison, M. S.
- Affiliations
- National Institute for Medical Research (GB)
- University of California, Davis (US)
- University of Milano-Bicocca (IT)
- Corresponding author
- Denison, Michael S.
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2009-06-04
- Volume
- 48
- Issue
- 25
- Pages
- 5972-5983
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- PMC
- PMC2859071
- OpenAlex
- W2131691673
- Semantic Scholar
- 3bf7962950f51258f21910624493c4173133a5bf
- Cited by
- 124
- References
- 58
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 6 · 2023: 8 · 2022: 4 · 2021: 10 · 2020: 7 · 2019: 12 · 2018: 4 · 2017: 5 · 2016: 7 · 2015: 7 · 2014: 8 · 2013: 6 · 2012: 8
- FWCI
- 8.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- Brunel University Research Archive (BURA) (Brunel University London) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- National Institute of Environmental Health Sciences (ES 07685, R01ES007685, ES012498, R01ES012498)
- Topics
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- aryl hydrocarbon receptor, TCDD, ligand-binding domain, PAS-B domain, conserved residues, homology modeling, site-directed mutagenesis, molecular docking, transcription factor activation, DNA binding
- MeSH terms
- Polychlorinated Dibenzodioxins, Amino Acid Sequence, Animals, Binding Sites, DNA-Binding Proteins, Guinea Pigs, Cricetinae, Ligands, Models, Molecular, Molecular Sequence Data, Peptide Mapping, Protein Binding, Rabbits, Structure-Activity Relationship, Mutagenesis, Site-Directed, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Receptors, Aryl Hydrocarbon, Mice, Rats
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