A Structural Switch between Agonist and Antagonist Bound Conformations for a Ligand-Optimized Model of the Human Aryl Hydrocarbon Receptor Ligand Binding Domain
Open accessAbstract
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates the expression of a diverse group of genes. Exogenous AHR ligands include the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is a potent agonist, and the synthetic AHR antagonist N-2-(1H-indol-3yl)ethyl)-9-isopropyl-2- (5-methylpyridin-3-yl)-9H-purin-6-amine (GNF351). As no experimentally determined structure of the ligand binding domain exists, homology models have been utilized for virtual ligand screening (VLS) to search for novel ligands. Here, we have developed an “agonist-optimized” homology model of the human AHR ligand binding domain, and this model aided in the discovery of two human AHR agonists by VLS. In addition, we performed molecular dynamics simulations of an agonist TCDD-bound and antagonist GNF351-bound version of this model in order to gain insights into the mechanics of the AHR ligand-binding pocket. These simulations identified residues 307–329 as a flexible segment of the AHR ligand pocket that adopts discrete conformations upon agonist or antagonist binding. This flexible segment of the AHR may act as a structural switch that determines the agonist or antagonist activity of a given AHR ligand.
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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 [25]
In §2.2 (page unavailable), the ligand-bound HIF-2α crystal-template model identified only 1 of 16 known agonists, versus 14 of 16 for the ligand-optimized NMR-template model; the authors describe the crystal-based model as performing poorly. §§2.1–2.2 specify rigid docking with receptor atoms fixed. The paper optimized pocket side chains separately, but does not support the claim that receptor flexibility was included in docking calculations. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredRecent docking studies allowed prediction of the binding modes of several AhR ligands and led to the discovery of novel AhR agonists and SAhRMs.
“On the basis of these novel approaches, recent docking studies not only allowed prediction of the binding modes of several AhR ligands but also led to the discovery of novel AhR agonists and SAhRMs25,27–30.”
From Modeling the binding of diverse ligands within the Ah receptor ligand binding domain (2019) · cites this paper as [25]
The Introduction and Results §3.1 describe docking-based predictions of binding interactions for several AhR ligands, and the Introduction says virtual screening identified novel agonists confirmed in cell-based assays. The paper does not report discovering novel SAhRMs; the Conclusions instead describe discovery of AhR modulators as a future prospect. No page numbers are provided in our copy. (LLM, conf=0.88)
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BackgroundMolecular dynamics simulation of the docking of substrates to proteins
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“Interestingly, the ability of the Met-P to interact with His291 and Ser365 agrees with experimental data showing that the agonistic effects of AhR binders is mediated by the interaction with these two keys residues [31,32,34].”
BackgroundEvidence of selective activation of aryl hydrocarbon receptor nongenomic calcium signaling by pyrene
Brinchmann, B. C., Ferrec, E. L., Bisson, W. H., Podechard, N., Huitfeldt, H. S., Gallais, I., Sergent, O., Holme, J. A., Lagadic‐Gossmann, D., & Øvrevik, J. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.09.023 · Cited by 34 · see citing works
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“A close look at the structures of AhR ligands revealed that transformations of this kind are not characteristic for TCDD, FICZ, GNF351 and other AhR ligands (agonists or antagonists) [64], owing to the stability of these compounds’ molecular structures and the absence of any propensity to tautomeric conversions.”
BackgroundInfluentialLiang, S.-X., Zhang, Y., Bo, H., Duan, W., & Zhong, L. (2022) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2022.114478 · Cited by 23
Ah receptor ligands and their impacts on gut resilience: structure–activity effects
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“Molecular docking was run against the binding pocket of the FXRLBD as previously reported [44].”
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PCB126 Blocks the Thermogenic Beiging Response of Adipocytes
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“A number of “natural” AhR agonists have been identified (Jin et al. 2014; Perkins et al. 2014; Hubbard et al. 2015; Mulero-Navarro and Fernandez-Salguero 2016), many of which are derived from liver and gut microbiome metabolism of tryptophan or indole (Hubbard et al. 2015).”
BackgroundSelf-citationLoss of the aryl hydrocarbon receptor increases tumorigenesis in p53-deficient mice
Phillips, J. L., Löhr, C. V., Nguyen, B. D., Buermeyer, A. B., & Kolluri, S. K. (2022) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2022.116191 · Cited by 14 · see citing works
Self-citationAryl Hydrocarbon Receptor as an Anticancer Target: An Overview of Ten Years Odyssey
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“Consistent with previous study [27], the binding pocket of AHR was automatically searched and located at the center of the protein (Figure 3c) and occupied a mostly hydrophobic site (Figure 3e).”
ResultElson, D. J., Nguyen, B. D., Wood, R., Zhang, Y., Puig-Sanvicens, V., & Kolluri, S. K. (2022) · FEBS Letters · doi:10.1002/1873-3468.14434 · Cited by 11 · see citing works
Self-citationAryl Hydrocarbon Receptor: A Bridge Linking Immuno-inflammation and Metabolism in Atherosclerosis.
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“Therefore, some molecules are AhR agonists, such as 2,3,7,8-tetrachlorodibenzodioxin (TCDD) or tryptophan metabolites, and others act as antagonists, such as UroA and baicalin (Faber et al., 2018; Muku et al., 2018).”
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Activation mechanism of AhR pathway in intestinal epithelial cells by commensal bacteria
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New cancer cells apoptosis agents: Fluorinated aza-heterocycles
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“21 TBHQ acts as an inducer of the Nrf2-Keap1 antioxidant system, which is enabled by increasing the stability of Nrf2 (Figure 1).”
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“Previous studies have also employed HIF-2α PAS-B as a template for AhR homology modeling, supporting its suitability for structural prediction [12, 59].”
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What Makes a Good Antagonist: Lessons Learned from the Estrogen and Aryl Hydrocarbon Receptors
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- Authors
- Perkins, A., Phillips, J., Kerkvliet, N., Tanguay, R., Perdew, G., Kolluri, S., & Bisson, W.
- Affiliations
- Oregon State University (US)
- Pennsylvania State University (US)
- Corresponding author
- Kolluri, Siva
- Bisson, William
- ORCID
- Venue
- Biology
- Publisher
- MDPI AG
- Published
- 2014-10-17
- Volume
- 3
- Issue
- 4
- Pages
- 645-669
- ISSN
- 2079-7737 (ISSN-L)
- PMC
- PMC4280506
- OpenAlex
- W2088241167
- Cited by
- 52
- References
- 42
- Citations by year
- 2026: 2 · 2024: 1 · 2023: 7 · 2022: 5 · 2021: 4 · 2020: 2 · 2019: 8 · 2018: 4 · 2017: 8 · 2016: 5 · 2015: 6
- FWCI
- 2.60
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- Biology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Oregon State University (P42 ES016465, P30ES000210)
- National Institute of Environmental Health Sciences (R01ES016651, R01ES004869, P30ES000210, R01ES019964, R21ES019000, P42ES016465)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- aryl hydrocarbon receptor, ligand-binding domain, homology modeling, virtual ligand screening, 2,3,7,8-tetrachlorodibenzo-p-dioxin, molecular dynamics simulation, transcription factors
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