Structural and mechanistic insights into bisphenols action provide guidelines for risk assessment and discovery of bisphenol A substitutes
Open Access
- 27 August 2012
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (37), 14930-14935
- https://doi.org/10.1073/pnas.1203574109
Abstract
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) α and β differ from that used by 17β-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 17β-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 γ 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.Keywords
This publication has 48 references indexed in Scilit:
- Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptorsProceedings of the National Academy of Sciences of the United States of America, 2012
- Effects of bisphenol A and triclocarban on brain-specific expression of aromatase in early zebrafish embryosProceedings of the National Academy of Sciences of the United States of America, 2011
- Coupling of receptor conformation and ligand orientation determine graded activityNature Chemical Biology, 2010
- Structural Overview of the Nuclear Receptor Superfamily: Insights into Physiology and TherapeuticsAnnual Review of Physiology, 2010
- Bisphenol A: Perinatal exposure and body weightMolecular and Cellular Endocrinology, 2009
- @TOME-2: a new pipeline for comparative modeling of protein-ligand complexesNucleic Acids Research, 2009
- NFκB selectivity of estrogen receptor ligands revealed by comparative crystallographic analysesNature Chemical Biology, 2008
- Modulators of the structural dynamics of the retinoid X receptor to reveal receptor functionProceedings of the National Academy of Sciences of the United States of America, 2007
- In vivo effects of bisphenol A in laboratory rodent studiesReproductive Toxicology, 2007
- Principles for modulation of the nuclear receptor superfamilyNature Reviews Drug Discovery, 2004