Sequence to Structure Approach of Estrogen Receptor Alpha and Ligand Interactions

Chamkasem, Aekkapot; Toniti, Waraphan

doi:10.7314/apjcp.2015.16.6.2161

Cited by 10 publications

(5 citation statements)

References 48 publications

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“…By contrast, the previous study using human ERα luciferase reporter gene assay revealed that none of these metabolites displayed estrogenic potency . This may be attribute to the difference between the rat and human ERα, despite the very similar sequence of these two receptor …”

Section: Discussionmentioning

confidence: 61%

“…26 This may be attribute to the difference between the rat and human ERα, despite the very similar sequence of these two receptor. 39 As for MR, the parent TDCIPP and TPHP inhibited MR signaling, and TCIPP has no interaction with MR. 21 The antagonistic potency of BDCIPP was roughly 21-fold higher than its parent chemical. Also, the BCIPP developed its antagonistic effect on MR at a low concentration (RIC 20 = 8.1 × 10 −7 M).…”

Section: Discussionmentioning

confidence: 99%

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New Insights in the Endocrine Disrupting Effects of Three Primary Metabolites of Organophosphate Flame Retardants

Zhang

Chang

et al. 2020

Environ. Sci. Technol.

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Despite the ubiquity of organophosphate flame retardants (OPFRs) metabolites in the biota, the endocrine disrupting potency has not been well examined. Herein, we chose three primary metabolites of OPFRs (BCIPP, BDCIPP, and DPHP) to investigate their potential endocrine disrupting effects by in vitro, in vivo, and in silico assays. Three metabolites were agonistic to rat estrogenic receptor alpha (ERα) and antagonists to human mineralocorticoid receptor (MR). BCIPP exerted endocrine disrupting effect contrasting to the negative response of its parental compound. It also poses the strongest binding capacity to ERα among the tested compounds. Both BCIPP and BDCIPP upregulated the genes encoded for estrogenic synthesis enzymes in H295R cells, including 17βHSD and CYP19. All three compounds stimulated the transcription of CYP11B1, whereas BCIPP and DPHP also triggered CYP11B2, encoding for corticoid production. BDCIPP inhibits genes for progesterone synthesis including CYP11A1, STAR, and 3-βHSD. The induction of mortality and low hatchability of zebrafish embryo were ranked as BCIPP ≥ BDCIPP > DPHP. All compounds lead to malformation of zebrafish larvae. Both of the hypothalamic-pituitary-adrenocortical and hypothalamic-pituitary−gonadal axes were disrupted, with the highest impact by BCIPP. Altogether, the data clarified OPFRs metabolites may produce comparable or even higher endocrine disrupting effects than OPFRs.

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

New Insights in the Endocrine Disrupting Effects of Three Primary Metabolites of Organophosphate Flame Retardants

Zhang

Chang

et al. 2020

Environ. Sci. Technol.

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“…Owing to the high degree of sequence identity between the human and rodent ERα-LBD proteins, it has been tacitly assumed that the 3D structures and ligand-binding characteristics of these receptors are essentially identical across species [75, 76]. Indeed, in tests of estrogenic potential, a common scenario is to conduct ligand-binding assays using human receptors in vitro and to carry out in vivo assessments in rodents [77–80].…”

Section: Discussionmentioning

confidence: 99%

Homology models of mouse and rat estrogen receptor-α ligand-binding domain created by in silico mutagenesis of a human template: Molecular docking with 17β-estradiol, diethylstilbestrol, and paraben analogs

Gonzalez

Rae

Colacino

et al. 2019

Computational Toxicology

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Crystal structures exist for human, but not rodent, estrogen receptor-α ligand-binding domain (ERα-LBD). Consequently, rodent studies involving binding of compounds to ERα-LBD are limited in their molecular-level interpretation and extrapolation to humans. Because the sequences of rodent and human ERα-LBDs are > 95% identical, we expected their 3D structures and ligand binding to be highly similar. To test this hypothesis, we used the human ERα-LBD structure (PDB 3UUD) as a template to produce rat and mouse homology models. Employing the rodent models and human structure, we generated docking poses of 23 Group A ligands (17ß-estradiol, diethylstilbestrol, and 21 paraben analogs) in AutoDock Vina for interspecies comparisons. Ligand RMSDs (Å) (median, 95% CI) were 0.49 (0.21–1.82) (human-mouse) and 1.19 (0.22–1.82) (human-rat), well below the 2.0–2.5 Å range for equivalent docking poses. Numbers of interspecies ligand-receptor residue contacts were highly similar, with Sorensen Sc (%) = 96.8 (90.0–100) (human-mouse) and 97.7 (89.5–100) (human-rat). Likewise, numbers of interspecies ligand-receptor residue contacts were highly correlated: Pearson r = 0.913 (human-mouse) and 0.925 (human-rat). Numbers of interspecies ligand-receptor atom contacts were even more tightly correlated: r = 0.979 (human-mouse) and 0.986 (human-rat). Pyramid plots of numbers of ligand-receptor atom contacts by residue exhibited high interspecies symmetry and had Spearman rs = 0.977 (human-mouse) and 0.966 (human-rat). Group B ligands included 15 ring-substituted parabens recently shown experimentally to exhibit decreased binding to human ERα and to exert increased antimicrobial activity. Ligand efficiencies calculated from docking ligands into human ERα-LBD were well correlated with those derived from published experimental data (Pearson partial rp = 0.894 and 0.918; Groups A and B, respectively). Overall, the results indicate that our constructed rodent ERα-LBDs interact with ligands in like manner to the human receptor, thus providing a high level of confidence in extrapolations of rodent to human ligand-receptor interactions.

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“…We characterized, in some detail, the effects of two of these five drugs, hexestrol and clomifene, as, in addition to efficiently suppressing the growth defect of the msp1 P300S strain, they present less toxicity at high concentrations. Hexestrol has been used for years to treat estrogen deficiency and is one of the most potent known estrogens (Chamkasem and Toniti, 2015; Solmssen, 1945). Clomifene induces ovulation and has been used as such to treat various cases of female infertility (Kistner, 1965; Wilkes and Murdoch, 2012).…”

Section: Discussionmentioning

confidence: 99%

A yeast-based screening assay identifies repurposed drugs that suppress mitochondrial fusion and mtDNA maintenance defects

Delerue

Tribouillard-Tanvier

Daloyau

et al. 2019

Disease Models &Amp; Mechanisms

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Mitochondria continually move, fuse and divide, and these dynamics are essential for the proper function of the organelles. Indeed, the dynamic balance of fusion and fission of mitochondria determines their morphology and allows their immediate adaptation to energetic needs as well as preserving their integrity. As a consequence, mitochondrial fusion and fission dynamics and the proteins that control these processes, which are conserved from yeast to human, are essential, and their disturbances are associated with severe human disorders, including neurodegenerative diseases. For example, mutations in OPA1 , which encodes a conserved factor essential for mitochondrial fusion, lead to optic atrophy 1, a neurodegeneration that affects the optic nerve, eventually leading to blindness. Here, by screening a collection of ∼1600 repurposed drugs on a fission yeast model, we identified five compounds able to efficiently prevent the lethality associated with the loss of Msp1p, the fission yeast ortholog of OPA1. One compound, hexestrol, was able to rescue both the mitochondrial fragmentation and mitochondrial DNA (mtDNA) depletion induced by the loss of Msp1p, whereas the second, clomifene, only suppressed the mtDNA defect. Yeast has already been successfully used to identify candidate drugs to treat inherited mitochondrial diseases; this work may therefore provide useful leads for the treatment of optic atrophies such as optic atrophy 1 or Leber hereditary optic neuropathy.

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Sequence to Structure Approach of Estrogen Receptor Alpha and Ligand Interactions

Cited by 10 publications

References 48 publications

New Insights in the Endocrine Disrupting Effects of Three Primary Metabolites of Organophosphate Flame Retardants

New Insights in the Endocrine Disrupting Effects of Three Primary Metabolites of Organophosphate Flame Retardants

Homology models of mouse and rat estrogen receptor-α ligand-binding domain created by in silico mutagenesis of a human template: Molecular docking with 17β-estradiol, diethylstilbestrol, and paraben analogs

A yeast-based screening assay identifies repurposed drugs that suppress mitochondrial fusion and mtDNA maintenance defects

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