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Phytoestrogens and Mycoestrogens Induce Signature Structure Dynamics Changes on Estrogen Receptor α

View Article: PubMed Central - PubMed

ABSTRACT

Endocrine disrupters include a broad spectrum of chemicals such as industrial chemicals, natural estrogens and androgens, synthetic estrogens and androgens. Phytoestrogens are widely present in diet and food supplements; mycoestrogens are frequently found in grains. As human beings and animals are commonly exposed to phytoestrogens and mycoestrogens in diet and environment, it is important to understand the potential beneficial or hazardous effects of estrogenic compounds. Many bioassays have been established to study the binding of estrogenic compounds with estrogen receptor (ER) and provided rich data in the literature. However, limited assays can offer structure information with regard to the ligand/ER complex. Our current study surveys the global structure dynamics changes for ERα ligand binding domain (LBD) when phytoestrogens and mycoestrogens bind. The assay is based on the structure dynamics information probed by hydrogen deuterium exchange mass spectrometry and offers a unique viewpoint to elucidate the mechanism how phytoestrogens and mycoestrogens interact with estrogen receptor. The cluster analysis based on the hydrogen deuterium exchange (HDX) assay data reveals a unique pattern when phytoestrogens and mycoestrogens bind with ERα LBD compared to that of estradiol and synthetic estrogen modulators. Our study highlights that structure dynamics could play an important role in the structure function relationship when endocrine disrupters interact with estrogen receptors.

No MeSH data available.


ERαLBD-ligand HDX profiles overlaid onto the ER crystal structure of estradiol (PDB ID: 1ERE). The color legend shows the deuterium incorporation difference by subtracting deuterium incorporation content of holo ERαLBD from apo ERαLBD. The compound showing in the protein ligand complex is estradiol for presentation purpose, but not representing the other compounds analyzed in this study.
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ijerph-13-00869-f003: ERαLBD-ligand HDX profiles overlaid onto the ER crystal structure of estradiol (PDB ID: 1ERE). The color legend shows the deuterium incorporation difference by subtracting deuterium incorporation content of holo ERαLBD from apo ERαLBD. The compound showing in the protein ligand complex is estradiol for presentation purpose, but not representing the other compounds analyzed in this study.

Mentions: Based on previous X-ray crystallography characterization, helix 12 position could be critical to determine the agonism or antagonism of the ER ligand when binding with ER [25]. In the analysis of different phytoestrogen and mycoestrogen binding with ER by HDX, helix 12 shows various degree of protection upon ligand binding, which is consistent with the previous observation of genistein binding with ERαLBD [30]. It needs to be noted that, in our HDX experiment, the differential HDX binding protection percentage calculation is based on exchange times, which are different from the previous studies. So the absolute comparison of the differential HDX binding protection percentage from the current study to the previous study is not applicable and meaningful. The exchange times were chosen at 15 min and 1 h, compared to four exchange times in the previous studies (e.g., 1 min, 5 min, 30 min and 70 min). The HDX profile data is presented in Table 2. Various phytoestrogens induced different ER dynamic change across different regions. The differential HDX dynamics was presented by different color codes in Figure 3. It needs to be noted that the LBD structure does not necessary represent the real protein X-ray crystallography structure as not all PDB files are available for each compound. The original estradiol and ERαLBD PDB structure is used for presentation purposes. The ligand in the binding pocket is estradiol but this does not represent the real chemical structure for other chemicals in this study. Consistent with the previous observations [27], the β-sheet 1/β-sheet 2 and helix 3 regions represent the regions that are generally impacted by the ligand binding in all the complexes.


Phytoestrogens and Mycoestrogens Induce Signature Structure Dynamics Changes on Estrogen Receptor α
ERαLBD-ligand HDX profiles overlaid onto the ER crystal structure of estradiol (PDB ID: 1ERE). The color legend shows the deuterium incorporation difference by subtracting deuterium incorporation content of holo ERαLBD from apo ERαLBD. The compound showing in the protein ligand complex is estradiol for presentation purpose, but not representing the other compounds analyzed in this study.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5036702&req=5

ijerph-13-00869-f003: ERαLBD-ligand HDX profiles overlaid onto the ER crystal structure of estradiol (PDB ID: 1ERE). The color legend shows the deuterium incorporation difference by subtracting deuterium incorporation content of holo ERαLBD from apo ERαLBD. The compound showing in the protein ligand complex is estradiol for presentation purpose, but not representing the other compounds analyzed in this study.
Mentions: Based on previous X-ray crystallography characterization, helix 12 position could be critical to determine the agonism or antagonism of the ER ligand when binding with ER [25]. In the analysis of different phytoestrogen and mycoestrogen binding with ER by HDX, helix 12 shows various degree of protection upon ligand binding, which is consistent with the previous observation of genistein binding with ERαLBD [30]. It needs to be noted that, in our HDX experiment, the differential HDX binding protection percentage calculation is based on exchange times, which are different from the previous studies. So the absolute comparison of the differential HDX binding protection percentage from the current study to the previous study is not applicable and meaningful. The exchange times were chosen at 15 min and 1 h, compared to four exchange times in the previous studies (e.g., 1 min, 5 min, 30 min and 70 min). The HDX profile data is presented in Table 2. Various phytoestrogens induced different ER dynamic change across different regions. The differential HDX dynamics was presented by different color codes in Figure 3. It needs to be noted that the LBD structure does not necessary represent the real protein X-ray crystallography structure as not all PDB files are available for each compound. The original estradiol and ERαLBD PDB structure is used for presentation purposes. The ligand in the binding pocket is estradiol but this does not represent the real chemical structure for other chemicals in this study. Consistent with the previous observations [27], the β-sheet 1/β-sheet 2 and helix 3 regions represent the regions that are generally impacted by the ligand binding in all the complexes.

View Article: PubMed Central - PubMed

ABSTRACT

Endocrine disrupters include a broad spectrum of chemicals such as industrial chemicals, natural estrogens and androgens, synthetic estrogens and androgens. Phytoestrogens are widely present in diet and food supplements; mycoestrogens are frequently found in grains. As human beings and animals are commonly exposed to phytoestrogens and mycoestrogens in diet and environment, it is important to understand the potential beneficial or hazardous effects of estrogenic compounds. Many bioassays have been established to study the binding of estrogenic compounds with estrogen receptor (ER) and provided rich data in the literature. However, limited assays can offer structure information with regard to the ligand/ER complex. Our current study surveys the global structure dynamics changes for ERα ligand binding domain (LBD) when phytoestrogens and mycoestrogens bind. The assay is based on the structure dynamics information probed by hydrogen deuterium exchange mass spectrometry and offers a unique viewpoint to elucidate the mechanism how phytoestrogens and mycoestrogens interact with estrogen receptor. The cluster analysis based on the hydrogen deuterium exchange (HDX) assay data reveals a unique pattern when phytoestrogens and mycoestrogens bind with ERα LBD compared to that of estradiol and synthetic estrogen modulators. Our study highlights that structure dynamics could play an important role in the structure function relationship when endocrine disrupters interact with estrogen receptors.

No MeSH data available.