Bisphenol A (BPA) binding on full‐length architectures of estrogen receptor

Abstract

Previous research has shown that the major toxicity mechanism for many environment chemicals is binding with estrogen receptor (ER) and blocking endogenous estrogen access, including bisphenol A (BPA). However, the molecular level understanding the global consequence of BPA binding on the full-length architectures of ER is largely unknown, which is a necessary stage to evaluate estrogen-like toxicity of BPA. In the present work, the consequence of BPA on full-length architectures of ER was firstly modeled based on molecular dynamics, focusing on the cross communication between multi-domains including ligand binding domain (LBD) and DNA binding domain (DBD). The study proved consequence of BPA upon full-length ER structure was dependent on long-range communications between multiple protein domains. The allosteric effects occurring in LBD units could alter dimerization formation through a crucial change in residue-residue connections, which resulted in relaxation of DBD. It indicated BPA could present consequence on the full-size receptor, not only on the separate domains, but also on the cross communication among LBD, DBD, and DNA molecules. It might provide detailed insight into the knowledge about the structural characteristics of ER and its role in gene regulation, which eventually helped us evaluate the estrogen-like toxicity upon BPA binding with full-length ER.

Machine Learning for Investigation on Endocrine-Disrupting Chemicals with Gestational Age and Delivery Time in a Longitudinal Cohort

“…For example, bisphenol A causes a decrease in the level of circulating testosterone in the human and rat [ 38 ]. EDCs have been shown to affect signal transduction in EH-responsive and EH receptor expression [ 10 , 26 ]. Evidence also shows the ability of EDCs to cause increased inflammation and oxidative stress that affect gestational age [ 37 ].…”

“…Exposure to EDCs such as bisphenol A, phthalates, has been suggested as a possible cause of pregnancy complications because of the harmful impact on reproductive and endocrine systems [ 8 , 9 ]. Bisphenol A has been shown to affect endocrine functions by downregulating the expression of estrogen receptor, with the potential downstream effects of miscarriage and premature birth [ 10 , 11 ]. Phthalates can also bind to the estrogen receptors and disturb sex steroid hormones, resulting in adverse pregnancy outcomes such as decreased length of gestation [ 12 ].…”

Application of Various Molecular Modelling Methods in the Study of Estrogens and Xenoestrogens

“…A separate set of studies investigated BPAs with halogen substituents on the phenolic rings. All studies showed that a hydrogen bond with His524 for an agonist and with Thr347 for an antagonist was created, exactly as in the case of estradiol and 4-OH-tamoxifen, respectively [ 187 , 188 ]. What is more, just as for estradiol, the stability of helix H12 is crucial in halogenated BPAs–ER complexes [ 188 , 189 ].…”

“…One of the studies [ 185 ] showed that the allosteric effects in the LBD due to BPA binding could cause relaxation of the DBD and, therefore, alter ER’s function. Other researchers reported the influence of bisphenol compounds on the protein’s allosteric modulation, altering the Helix12 stability and reducing the recruitment potency of co-activators [ 187 ]. This knowledge can be useful in the process of estimating the toxicity of compounds.…”

Endocrine disruptors from the environment affecting breast cancer (Review)

“…Therefore, it has been proposed that BPA can serve as an allosteric modulator. Interestingly, this interference does not only affect the binding with the estrogen but also affects the communication between the ligand-binding domain (LBD) and the DNA binding domain (DBD) (56).…”