Structural Evidence for Endocrine Disruptor Bisphenol A Binding to Human Nuclear Receptor ERR 

Abstract

Many lines of evidence reveal that bisphenol A (BPA) functions at very low doses as an endocrine disruptor. The human estrogen-related receptor gamma (ERR gamma) behaves as a constitutive activator of transcription, although the endogenous ligand is unknown. We have recently demonstrated that BPA binds strongly to ERR gamma (K(D) = 5.5 nM), but not to the estrogen receptor (ER). BPA preserves the ERR gamma's basal constitutive activity, and protects the selective ER modulator 4-hydroxytamoxifen from its deactivation of ERR gamma. In order to shed light on a molecular mechanism, we carried out the X-ray analysis of crystal structure of the ERR gamma ligand-binding domain (LBD) complexed with BPA. BPA binds to the receptor cavity without changing any internal structures of the pocket of the ERR gamma-LBD apo form. The hydrogen bonds of two phenol-hydroxyl groups, one with both Glu275 and Arg316, the other with Asn346, anchor BPA in the pocket, and surrounding hydrophobic bonds, especially with Tyr326, complete BPA's strong binding. Maintaining the 'activation helix' (helix 12) in an active conformation would as a result preserve receptor constitutive activity. Our results present the first evidence that the nuclear receptor forms complexes with the endocrine disruptor, providing detailed molecular insight into the interaction features.

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

“…S15) and the crystal structure of ERRγ in complex with BPA (SI Appendix, Fig. S8C) (43,44). Therefore, it appears that most bisphenols are rather weak binders (i.e., micromolar range) of several NRs and that their binding mode varies according to their chemical structure as well as the receptor under scrutiny.…”

Nuclear receptors in transgenerational epigenetic inheritance

“…The IC50 for ERRγ of the BPA is 13.4nM, comparable to tamoxifen (10.3 nM) (Takayanagi et al, 2006). Regarding the ERRγ, not only do biochemical data confirm this effect but also the crystal structure of ERRγ with BPA is available (Matsushima et al, 2007). In very high concentrations (in the 100μM range) BPA was shown to activate AR, although the relevance of these data is questionable due to the fact that 100 μM is a concentration far too high represent an environmental pollutant (Li et al).…”

“…BPA is used in plastic ware, medical tubing, food and water containers and is considered one of the most important endocrine disruptors present in our environment. Immense quantities of it are produced, approximately 3.2 million tons per year (Matsushima et al, 2007). A detailed review on BPA and nuclear receptors can be read here (Delfosse et al) BPA is considered to an endocrine disruptor targeting ERα, although significant amounts of data suggest the involvement of other nuclear receptors in mediating the observed effects.…”

“…BPA seems to be a relatively promiscuous molecule, having an EC 50 of 4μM for ERα and ERβ, 2μM for RXRα and more than 10μM for PXR (le Maire et al) (Matsushima et al, 2007). Besides activating ERα, ERβ, RXRα and PXR, several lines of evidence underlie the importance of ERRγ in mediating the effects of BPA (Matsushima et al, 2007). BPA binds to the ERRγ molecule and preserves its basal transcriptional activity.…”

Need for Regulatory Policies in India, on the Use of Bisphenol a in Food Contact Plastic Containers

“…Thereafter, several studies also provided evidence on the endocrine disrupting action of BPA [18][19][20][21][22][23][24][25][26][27][28] . BPA is similar in function to the natural hormone 17-estradiol and binds mainly to the estrogen receptor (ER) to exhibit estrogenic activities 29,30 . Some of the chemicals such as bisphenol F (BPF) and bisphenol S (BPS) are generally used as alternatives in consumer products and labelled as 'BPA-free'.…”