Estradiol-like binding of brominated flame retardants to human estrogen sulfotransferase

Friday, November 08, 2013 — Poster Session IV
2:00 p.m. – 4:00 p.m.	FAES Academic Center (Upper-Level Terrace)	NIEHS	STRUCTBIO-6

Authors

R.A. Gosavi
G.A. Knudsen
L.S. Birnbaum
L.C. Pedersen

Abstract

Widespread use of brominated flame retardants (BFRs) in a number of consumer products has raised concern about their release into the environment from commercial products. Structurally similar to hormones, exposure to some of these chemicals may result in adverse effects, such as endocrine disruption. Certain BFRs have been shown to inhibit estrogen sulfotransferase (SULT1E1) potentially increasing levels of free estradiol (E2) in the system. In particular, Tetrabromobisphenol A (TBBPA) and 3OH-BDE47 (a human metabolite of bromodiphenyl ether) were shown to inhibit E2 sulfation by SULT1E1 with IC50 values in the range of 10-40 nM (Km E2 5nM). The primary goal of this study was to understand the structural mechanism for inhibition of SULT1E1, by BFRs. Our results include high resolution crystal structures of complexes of human SULT1E1 and PAP (adenosine-3'-5'-diphosphate) with TBBPA, 3OH-BDE47 and with E2. These structures reveal how structurally diverse TBBPA and 3OH-BDE47 exhibit minimal structural requirements for binding to the enzyme at the same site as E2. The structures show that the phenolic hydroxyl is a common feature and likely important for binding. Additionally, our results suggest how bromides on carbons adjacent to the phenolic hydroxyl are accommodated by the enzyme and contribute towards high affinity binding.