Ligand binding and activation of the Ah receptor

Denison, Michael S.; Pandini, Alessandro; Nagy, Scott R.; Baldwin, Enoch P.; Bonati, Laura

doi:10.1016/s0009-2797(02)00063-7

Cited by 417 publications

(305 citation statements)

References 129 publications

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“…The LBD of modeled AhR contained five ␤-sheets and one ␣-helix, which was in accordance with previous investigations (Denison et al, 2002;Pandini et al, 2007). A Ramachandran plot from PROCHECK ( Fig.…”

Section: Homologous Modeling and Molecular Docking Analysissupporting

confidence: 90%

Docking and 3D-QSAR studies on the Ah receptor binding affinities of polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs)

Liu

et al. 2011

Environmental Toxicology and Pharmacology

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Section: Homologous Modeling and Molecular Docking Analysissupporting

confidence: 90%

Docking and 3D-QSAR studies on the Ah receptor binding affinities of polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs)

Liu

et al. 2011

Environmental Toxicology and Pharmacology

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“…Upon binding to chemicals such as TCDD, the chaperones dissociate from the receptor, resulting in AhR translocating into the nucleus and dimerizing with ARNT (AhR nuclear translocator), which eventually leads to changes in gene transcription. 51 The physiological ligands of this receptor are still unknown, but it binds with several groups of exogenous ligands such as synthetic polycyclic aromatic hydrocarbons and dioxin-like compounds. 52,53 Results obtained from in vivo animal experiments suggest the possibility of dioxin-like behavior for PBDEs.…”

Section: Aryl Hydrocarbon Receptor Pathwaymentioning

confidence: 99%

Molecular toxicology of polybrominated diphenyl ethers: nuclear hormone receptor mediated pathways

Ren

Guo

2013

Environ. Sci.: Processes Impacts

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Polybrominated diphenyl ethers (PBDEs) are used in large quantities as flame retardant additives in commercial products. Bio-monitoring data show that PBDE concentrations have increased rapidly in the bodies of wildlife and human over the last few decades. Based on the studies on experimental animals, the toxicological endpoints of exposure to PBDEs are likely to be thyroid homeostasis disruption, neurodevelopmental deficits, reproductive ineffectiveness and even cancer. Unfortunately, the available molecular toxicological evidence for these endpoints is still very limited. This review focuses on the recent studies on the molecular mechanisms of PBDE toxicities carried out through the hormone receptor pathways, including thyroid hormone receptor, estrogen receptor, androgen receptor, progesterone receptor and aryl hydrocarbon receptor pathways. The general approach in the mechanistic investigation is to examine the in vitro direct binding of a PBDE with a receptor, the in vitro recruitment of a co-activator or co-repressor by the ligand-bound receptor, and the participation of the ligand in the receptor-mediated transcription pathways in cells. It is hoped that further studies in this area would provide more insights into the potential risks of PBDEs to human health. Environmental impactPBDEs are a class of chemicals used as ame retardant additives in a wide variety of industrial and commercial products. Rising levels of PBDEs have been detected in the human body. The toxicological endpoints of exposure to PBDEs are likely to be thyroid homeostasis disruption, neuro-developmental decits, reproductive ineffectiveness and even cancer. However, the available molecular toxicological evidence for these endpoints is still very limited. This review focuses on the recent studies on the molecular mechanisms of PBDE toxicities carried out through the hormone receptor pathways, including thyroid hormone receptor, estrogen receptor, androgen receptor, progesterone receptor and aryl hydrocarbon receptor pathways.

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“…Since the AhR from species that contain the A375V mutation naturally (i.e., human and DBA mice) can still function normally in a TCDD-dependent manner, albeit higher TCDD concentrations are required (6,16,17,24,63), it must still bind ligand. Given the documented lower affinity of the A375V mutation, we repeated the binding assay with this mutant AhR using 20 nM instead of 2 nM [ 3 H]TCDD (Table 4, .…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

Structural and Functional Characterization of the Aryl Hydrocarbon Receptor Ligand Binding Domain by Homology Modeling and Mutational Analysis

et al. 2006

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The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that is activated by a structurally diverse array of synthetic and natural chemicals, including toxic halogenated aromatic hydrocarbons such as 2, 3,7,. Analysis of the molecular events occurring in the AhR ligand binding and activation processes requires structural information on the AhR Per-Arnt-Sim (PAS) B-containing ligand binding domain, for which no experimentally determined structure has been reported. With the availability of extensive structural information on homologous PAS-containing proteins, a reliable model of the mouse AhR PAS B domain was developed by comparative modeling techniques. The PAS domain structures of the functionally related hypoxia-inducible factor 2α (HIF-2α) and AhR nuclear translocator (ARNT) proteins, which exhibit the highest degree of sequence identity and similarity with AhR, were chosen to develop a two-template model. To confirm the features of the modeled domain, the effects of point mutations in selected residue positions on both TCDD binding to the AhR and TCDD-dependent transformation and DNA binding were analyzed. Mutagenesis and functional analysis results are consistent with the proposed model and confirm that the cavity modeled in the interior of the domain is indeed involved in ligand binding. Moreover, the physicochemical characteristics of some residues and of their mutants, along with the effects of mutagenesis on TCDD and DNA binding, also suggest some key features that are required for ligand binding and activation of mAhR at a molecular level, thus providing a framework for further studies.The aryl hydrocarbon receptor (AhR) 1 is a basic helix-loop-helix (bHLH), PAS-(Per-ArntSim-) containing transcription factor which is present in numerous species and tissues and activates gene expression in a ligand-dependent manner (1-3). While the AhR can bind and be activated by a large number of structurally diverse chemicals (4-6), the highest affinity ligands include halogenated aromatic hydrocarbons (HAHs), such as 2, 3,7,8- NIH Public Access Author ManuscriptBiochemistry. Author manuscript; available in PMC 2010 April 28. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript tetrachlorodibenzo-p-dioxin (TCDD, dioxin), and polycyclic aromatic hydrocarbons (PAHs), both widespread classes of environmental contaminants (4,7). Mechanistically, the inducing chemical diffuses across the plasma membrane and binds to the cytosolic AhR which exists as a multiprotein complex containing two molecules of hsp90 (a heat shock protein of 90 kDa), the X-associated protein 2 (XAP2), and the cochaperone p23 (8).Following ligand binding, the AhR is presumed to undergo a conformational change (9), exposing an N-terminal nuclear localization sequence that leads to translocation of the liganded AhR complex into the nucleus (10). Dissociation of the AhR from the protein complex and its dimerization with ARNT (AhR nuclear translocator) convert the AhR complex into its high-affinity ...

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Ligand binding and activation of the Ah receptor

Cited by 417 publications

References 129 publications

Docking and 3D-QSAR studies on the Ah receptor binding affinities of polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs)

Docking and 3D-QSAR studies on the Ah receptor binding affinities of polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs)

Molecular toxicology of polybrominated diphenyl ethers: nuclear hormone receptor mediated pathways

Structural and Functional Characterization of the Aryl Hydrocarbon Receptor Ligand Binding Domain by Homology Modeling and Mutational Analysis

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