A structural view of nuclear hormone receptor: endocrine disruptor interactions

Abstract

Endocrine-disrupting chemicals (EDCs) represent a broad class of exogenous substances that cause adverse effects in the endocrine system by interfering with hormone biosynthesis, metabolism, or action. The molecular mechanisms of EDCs involve different pathways including interactions with nuclear hormone receptors (NHRs) which are primary targets of a large variety of environmental contaminants. Here, based on the crystal structures currently available in the Protein Data Bank, we review recent studies showing the many ways in which EDCs interact with NHRs and impact their signaling pathways. Like the estrogenic chemical diethylstilbestrol, some EDCs mimic the natural hormones through conserved protein-ligand contacts, while others, such as organotins, employ radically different binding mechanisms. Such structure-based knowledge, in addition to providing a better understanding of EDC activities, can be used to predict the endocrine-disrupting potential of environmental pollutants and may have applications in drug discovery.

Endocrine-disrupting chemicals in ovarian function: effects on steroidogenesis, metabolism and nuclear receptor signaling

“…By the 1970s, numerous studies showing multi-generational effects of DES on reproductive, cardiovascular, and immune systems lead to a ban on the use of this drug during pregnancy (Goldberg & Flacone 1999). DES mimics the natural estrogen, E 2 , through conserved protein-ligand contact and binds to both ESR1 and ESR2 with higher affinity than that of E 2 (Kuiper et al 1997, le Maire et al 2010. Animal studies have shown that neonatal exposure to DES (3 mg) induces abnormalities in the mouse ovary, including delayed folliculogenesis and polyovular follicles (Kim et al 2009b).…”

Azadirachtin Interacts with Retinoic Acid Receptors and Inhibits Retinoic Acid-mediated Biological Responses

“…Protein Preparation for Docking-RXR␣ was the crystal structure of RXR␣ ligand binding domain in complex with triphenyltin and a coactivator fragment (PDB code 3KWY) (27) retrieved from PDB. Before initiating the docking simulations, all non-protein molecules were removed from RXR␣; for any alternative atom locations only the first location (A) was retained.…”

Endocrine disrupting chemicals

“…Since some of the EDCs bear very similar chemical structures to the endogenous hormones, 91 the interaction between nuclear hormone receptors (NHRs) and EDCs has been proposed as the elementary action on endocrine disruption. 92,93 It is generally believed that EDCs can affect the hormonal system via (but not limited to) estrogenic, androgenic, anti-androgenic and anti-thyroid mechanisms. 30,94 The mechanistic aspects of endocrine disruption may be via the roles as (1) agonist or antagonist, (2) selective modulators in the recruitment of coactivators/co-repressor in transcriptional complex or/ and (3) in cross-talk between NHRs.…”