Modeling the binding of diverse ligands within the Ah receptor ligand binding domain

Tagliabue, Sara Giani; Faber, Samantha C.; Motta, Stefano; Denison, Michael S.; Bonati, Laura

doi:10.1038/s41598-019-47138-z

Cited by 77 publications

(58 citation statements)

References 70 publications

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“…The sequence alignment of top 10 templates used by I-TASSER to homology model of the hAhR LBD is illustrated in Figure 4C. In accordance with previous modelling approaches [13,27], I-TASSER also identified PAS structures as the best template for hAhR modelling, with about 50% of sequence similarity. Out of the five models generated by I-TASSER, the model with the highest C-Score (−0.05) was selected for further study.…”

Section: Molecular Docking Studiessupporting

confidence: 74%

“…Ligand-dependent activation of the AhR can result in an extremely diverse spectrum of biological and toxic effects that occur in a ligand-, species-and tissue-specific manner [26]. On the basis of a novel computational approach for molecular docking to the homology model of the AhR LBD, specific residues within the AhR binding cavity that play a critical role in binding of three distinct groups of chemicals were recently predicted and experimentally confirmed by Giani Tagliabue et al [27]. A ligand-selective structural hierarchy controlling dimerization of the AhR with ARNT and the recognition of target DNA was described by Seok et al [28].…”

Section: Discussionmentioning

confidence: 98%

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Antimigraine Drug Avitriptan Is a Ligand and Agonist of Human Aryl Hydrocarbon Receptor that Induces CYP1A1 in Hepatic and Intestinal Cells

Vyhlídalová

Krasulová

Pečinková

et al. 2020

IJMS

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The efforts for therapeutic targeting of the aryl hydrocarbon receptor (AhR) have emerged in recent years. We investigated the effects of available antimigraine triptan drugs, having an indole core in their structure, on AhR signaling in human hepatic and intestinal cells. Activation of AhR in reporter gene assays was observed for Avitriptan and to a lesser extent for Donitriptan, while other triptans were very weak or no activators of AhR. Using competitive binding assay and by homology docking, we identified Avitriptan as a low-affinity ligand of AhR. Avitriptan triggered nuclear translocation of AhR and increased binding of AhR in CYP1A1 promotor DNA, as revealed by immune-fluorescence microscopy and chromatin immune-precipitation assay, respectively. Strong induction of CYP1A1 mRNA was achieved by Avitriptan in wild type but not in AhR-knockout, immortalized human hepatocytes, implying that induction of CYP1A1 is AhR-dependent. Increased levels of CYP1A1 mRNA by Avitriptan were observed in human colon carcinoma cells LS180 but not in primary cultures of human hepatocytes. Collectively, we show that Avitriptan is a weak ligand and activator of human AhR, which induces the expression of CYP1A1 in a cell-type specific manner. Our data warrant the potential off-label therapeutic application of Avitriptan as an AhR-agonist drug.

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Section: Molecular Docking Studiessupporting

confidence: 74%

Section: Discussionmentioning

confidence: 98%

Antimigraine Drug Avitriptan Is a Ligand and Agonist of Human Aryl Hydrocarbon Receptor that Induces CYP1A1 in Hepatic and Intestinal Cells

Vyhlídalová

Krasulová

Pečinková

et al. 2020

IJMS

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“…Here, through the study of the candidate driver mutation AHR Q383H, we provided a validation of the accuracy of our prediction. The importance of Q383 site in AhR activity (Q377 as the mouse equivalent) was previously suggested by its structural impact on AhR ligand binding affinity and preference by shape and H-bond [ 76 – 78 ]. We showed that the AHR Q383H mutation and other genetic alterations affecting the AhR pathway ( AHR and ARNT amplifications) were associated with dependency to AHR expression or activity and were enriched in the luminal subtype of BCa.…”

Section: Discussionmentioning

confidence: 99%

Identification of new driver and passenger mutations within APOBEC-induced hotspot mutations in bladder cancer

et al. 2020

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Background APOBEC-driven mutagenesis and functional positive selection of mutated genes may synergistically drive the higher frequency of some hotspot driver mutations compared to other mutations within the same gene, as we reported for FGFR3 S249C. Only a few APOBEC-associated driver hotspot mutations have been identified in bladder cancer (BCa). Here, we systematically looked for and characterised APOBEC-associated hotspots in BCa. Methods We analysed 602 published exome-sequenced BCas, for part of which gene expression data were also available. APOBEC-associated hotspots were identified by motif-mapping, mutation signature fitting and APOBEC-mediated mutagenesis comparison. Joint analysis of DNA hairpin stability and gene expression was performed to predict driver or passenger hotspots. Aryl hydrocarbon receptor (AhR) activity was calculated based on its target genes expression. Effects of AhR knockout/inhibition on BCa cell viability were analysed. Results We established a panel of 44 APOBEC-associated hotspot mutations in BCa, which accounted for about half of the hotspot mutations. Fourteen of them overlapped with the hotspots found in other cancer types with high APOBEC activity. They mostly occurred in the DNA lagging-strand templates and the loop of DNA hairpins. APOBEC-associated hotspots presented systematically a higher prevalence than the other mutations within each APOBEC-target gene, independently of their functional impact. A combined analysis of DNA loop stability and gene expression allowed to distinguish known passenger from known driver hotspot mutations in BCa, including loss-of-function mutations affecting tumour suppressor genes, and to predict new candidate drivers, such as AHR Q383H. We further characterised AHR Q383H as an activating driver mutation associated with high AhR activity in luminal tumours. High AhR activity was also found in tumours presenting amplifications of AHR and its co-receptor ARNT. We finally showed that BCa cells presenting those different genetic alterations were sensitive to AhR inhibition. Conclusions Our study identified novel potential drivers within APOBEC-associated hotspot mutations in BCa reinforcing the importance of APOBEC mutagenesis in BCa. It could allow a better understanding of BCa biology and aetiology and have clinical implications such as AhR as a potential therapeutic target. Our results also challenge the dogma that all hotspot mutations are drivers and mostly gain-of-function mutations affecting oncogenes.

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“…Finally, citrate binding to the PAS domain of sensor histidine kinase CitA was shown to induce a flexion of the central β-sheet around the ligand that then propagates to the transmembrane domain of the protein [29]. 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 understood.…”

Section: Introductionmentioning

confidence: 99%

Transitional States in Ligand-Dependent Transformation of the Aryl Hydrocarbon Receptor into Its DNA-Binding Form

Soshilov

Motta

Bonati

et al. 2020

IJMS

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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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Modeling the binding of diverse ligands within the Ah receptor ligand binding domain

Cited by 77 publications

References 70 publications

Antimigraine Drug Avitriptan Is a Ligand and Agonist of Human Aryl Hydrocarbon Receptor that Induces CYP1A1 in Hepatic and Intestinal Cells

Antimigraine Drug Avitriptan Is a Ligand and Agonist of Human Aryl Hydrocarbon Receptor that Induces CYP1A1 in Hepatic and Intestinal Cells

Identification of new driver and passenger mutations within APOBEC-induced hotspot mutations in bladder cancer

Transitional States in Ligand-Dependent Transformation of the Aryl Hydrocarbon Receptor into Its DNA-Binding Form

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