A Structural Switch between Agonist and Antagonist Bound Conformations for a Ligand-Optimized Model of the Human Aryl Hydrocarbon Receptor Ligand Binding Domain

Perkins, Arden; Phillips, Jessica; Kerkvliet, Nancy I.; Tanguay, Robert L.; Perdew, Gary H.; Kolluri, Siva Kumar; Bisson, William H.

doi:10.3390/biology3040645

Cited by 43 publications

(52 citation statements)

References 40 publications

(92 reference statements)

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“…The antiestrogen raloxifene induced apoptosis in TNBC cells indicating that this compound or its analogs also have potential as AhR-targeted therapeutics for breast cancer therapy (O’Donnell et al 2014). Focused virtual ligand screening utilizing AhR ligand binding pocket models may help to identify such compounds (Bisson et al 2009; Perkins et al 2014). …”

Section: The Ahr and Its Ligand In Tumorigenesis And Cancer Chemotherapymentioning

confidence: 99%

Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target

2017

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The aryl hydrocarbon receptor (AhR) was initially identified as the receptor that binds and mediates the toxic effects induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and structurally related halogenated aromatics. Other toxic compounds including some polynuclear aromatic hydrocarbons act through the AhR; however, during the last 25 years, it has become apparent that the AhR plays an essential role in maintaining cellular homeostasis. Moreover, the scope of ligands that bind the AhR includes endogenous compounds such as multiple tryptophan metabolites, other endogenous biochemicals, pharmaceuticals and health-promoting phytochemicals including flavonoids, indole-3-carbinol and its metabolites. It has also been shown that like other receptors, the AhR is a drug target for multiple diseases including cancer, where both AhR agonists and antagonists effectively block many of the critical hallmarks of cancer in multiple tumor types. This review describes the anti-cancer activities of AhR ligands and demonstrates that it is time to separate the AhR from TCDD and exploit the potential of the AhR as a novel target for cancer chemotherapy.

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Section: The Ahr and Its Ligand In Tumorigenesis And Cancer Chemotherapymentioning

confidence: 99%

Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target

2017

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“…For clarity, the numbers of the relevant amino acids in PDB ID 1OT7 file, Arg328, Ser329, and Tyr366, have been adjusted as Arg331, Ser332, and Tyr369 (UniRef100_B6ZGS9). Molecular docking was run against the binding pocket of the FXR-LBD as previously reported [44]. The docking protocol was initially validated by docking 3-deoxy-CDCA into the FXR-LBD.…”

Section: Methodsmentioning

confidence: 99%

Conformational modulation of the farnesoid X receptor by prenylflavonoids: Insights from hydrogen deuterium exchange mass spectrometry (HDX-MS), fluorescence titration and molecular docking studies

Yang

Broderick

Campbell

et al. 2016

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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We report on the molecular interactions of the Farnesoid X Receptor (FXR) with prenylflavonoids, an emerging class of FXR modulators. FXR is an attractive therapeutic target for mitigating metabolic syndromes (MetS) because FXR activates the inhibitory nuclear receptor, small heterodimer partner (SHP), thereby inhibiting both gluconeogenesis and de novo lipogenesis. We and others have shown that xanthohumol (XN), the principal prenylflavonoid of the hop plant (Humulus lupulus L.), is a FXR agonist based on its ability to affect lipid and glucose metabolism in vivo and to induces FXR target genes in biliary carcinoma cells and HEK293 cells. However, studies are currently lacking to rationalize the molecular mechanisms of FXR modulation by prenylflavonoids. We addressed this deficiency and report the first systematic study of FXR prenylflavonoid interactions. We combined Hydrogen Deuterium Exchange Mass Spectrometry (HDX-MS) with computational studies for dissecting molecular recognition and conformational impact of prenylflavonoid interactions on the ligand binding domain (LBD) of human FXR. Four prenylflavonoids were tested: xanthohumol, a prenylated chalcone, two prenylated flavonones, namely isoxanthohumol (IX) and 8-prenylnaringenin (8PN), and a semisynthetic prenylflavonoid derivative, tetrahydroxanthohumol (TX). Enhancement of the HDX protection profile data by in silico predicted models of FXR prenylflavonoid complexes resulted in mapping of the prenylflavonoid interactions within the canonical ligand binding pocket. Our findings provide a foundation for the exploration of the chemical scaffolds of prenylated chalcones and flavanones as leads for future structure activity studies of this important nuclear receptor with potential relevance for ameliorating lipid metabolic disorders associated with obesity and MetS.

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“…The homology model of the human AhR-PASB-LBD is based on the nuclear magnetic resonance (NMR) apo structure of the Hypoxia inducible factor (HIF)-2a Per-ARNT-Sim-B (PASB) domain Protein database (PDB 1P97) was prepared and optimized as described (Perkins, et al 2014). Molecular docking was run as previously described (Hubbard, et al 2015).…”

Section: In Silico Molecular Modelingmentioning

confidence: 99%

Divergent Ah Receptor Ligand Selectivity during Hominin Evolution

et al. 2016

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We have identified a fixed nonsynonymous sequence difference between humans (Val381; derived variant) and Neandertals (Ala381; ancestral variant) in the ligand-binding domain of the aryl hydrocarbon receptor (AHR) gene. In an exome sequence analysis of four Neandertal and Denisovan individuals compared with nine modern humans, there are only 90 total nucleotide sites genome-wide for which archaic hominins are fixed for the ancestral nonsynonymous variant and the modern humans are fixed for the derived variant. Of those sites, only 27, including Val381 in the AHR, also have no reported variability in the human dbSNP database, further suggesting that this highly conserved functional variant is a rare event. Functional analysis of the amino acid variant Ala381 within the AHR carried by Neandertals and nonhuman primates indicate enhanced polycyclic aromatic hydrocarbon (PAH) binding, DNA binding capacity, and AHR mediated transcriptional activity compared with the human AHR. Also relative to human AHR, the Neandertal AHR exhibited 150-1000 times greater sensitivity to induction of Cyp1a1 and Cyp1b1 expression by PAHs (e.g., benzo(a)pyrene). The resulting CYP1A1/CYP1B1 enzymes are responsible for PAH first pass metabolism, which can result in the generation of toxic intermediates and perhaps AHR-associated toxicities. In contrast, the human AHR retains the ancestral sensitivity observed in primates to nontoxic endogenous AHR ligands (e.g., indole, indoxyl sulfate). Our findings reveal that a functionally significant change in the AHR occurred uniquely in humans, relative to other primates, that would attenuate the response to many environmental pollutants, including chemicals present in smoke from fire use during cooking.

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A Structural Switch between Agonist and Antagonist Bound Conformations for a Ligand-Optimized Model of the Human Aryl Hydrocarbon Receptor Ligand Binding Domain

Cited by 43 publications

References 40 publications

Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target

Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target

Conformational modulation of the farnesoid X receptor by prenylflavonoids: Insights from hydrogen deuterium exchange mass spectrometry (HDX-MS), fluorescence titration and molecular docking studies

Divergent Ah Receptor Ligand Selectivity during Hominin Evolution

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