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Structural and mechanistic insights into bisphenols action provide guidelines for risk assessment and discovery of bisphenol A substitutes.

Authors: Delfosse, V  Grimaldi, M  Pons, JL  Boulahtouf, A  Le Maire, A  Cavailles, V  Labesse, G  Bourguet, W  Balaguer, P 
Citation: Delfosse V, etal., Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):14930-5. doi: 10.1073/pnas.1203574109. Epub 2012 Aug 27.
Pubmed: (View Article at PubMed) PMID:22927406
DOI: Full-text: DOI:10.1073/pnas.1203574109

Bisphenol A (BPA) is an industrial compound and a well known endocrine-disrupting chemical with estrogenic activity. The widespread exposure of individuals to BPA is suspected to affect a variety of physiological functions, including reproduction, development, and metabolism. Here we report that the mechanisms by which BPA and two congeners, bisphenol AF and bisphenol C (BPC), bind to and activate estrogen receptors (ER) alpha and beta differ from that used by 17beta-estradiol. We show that bisphenols act as partial agonists of ERs by activating the N-terminal activation function 1 regardless of their effect on the C-terminal activation function 2, which ranges from weak agonism (with BPA) to antagonism (with BPC). Crystallographic analysis of the interaction between bisphenols and ERs reveals two discrete binding modes, reflecting the different activities of compounds on ERs. BPA and 17beta-estradiol bind to ERs in a similar fashion, whereas, with a phenol ring pointing toward the activation helix H12, the orientation of BPC accounts for the marked antagonist character of this compound. Based on structural data, we developed a protocol for in silico evaluation of the interaction between bisphenols and ERs or other members of the nuclear hormone receptor family, such as estrogen-related receptor gamma and androgen receptor, which are two known main targets of bisphenols. Overall, this study provides a wealth of tools and information that could be used for the development of BPA substitutes devoid of nuclear hormone receptor-mediated activity and more generally for environmental risk assessment.

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CRRD Object Information
CRRD ID: 8547944
Created: 2014-03-03
Species: All species
Last Modified: 2014-03-03
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.