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.

Fig. 1

Chemical structures of representative EDCs discussed in this review. E2 17β-estradiol, DES diethylstilbestrol, GEN genistein, PhIP 2-amino-1-methyl-6-phenylimidazo [4-5-b] pyridine, 4-OH-PhIP 4-hydroxy-2-amino-1-methyl-6-phenylimidazo [4-5-b] pyridine, ZEN zearalenone, BPA bisphenol A, 9-cis RA 9-cis retinoic acid, TBT tributyltin, TPT triphenyltin, MA methoprene acid

Fig. 2

Schematic illustration of the structural and functional organization of NHRs. a NHRs contain a well-conserved DNA binding domain (DBD), a moderately conserved ligand binding domain (LBD), and a highly divergent N-terminal A/B region. Two transcriptional activation functions have been described in these receptors: a “constitutively active” AF-1 in region A/B and an AF-2 which corresponds to a coactivator binding surface formed by helices H3, H4, and H12 of the LBD whose completion requires the presence of the hormone. b Overall structure of NHR LBDs exemplified by the ERα LBD homodimer (PDB code 1GWR) in complex with estradiol (stick representation) and a coactivator fragment (CoA). H1–H12 and s1, s2 denote α-helices and β-strands, respectively

Fig. 3

Structural determinants of ligand recognition by ERs. a Close-up view of the E2 binding pocket in ERα (PDB code 1GWR). ERα residues involved in hormone binding as well as the E2 molecule are colored in yellow. b Superposition of ERα and ERβ LBPs in complex with E2 (yellow, PDB code 1GWR) and GEN (blue, PDB code 1QKM), respectively. Residues involved in E2 and GEN binding are colored in yellow and blue, respectively. c Close-up view of the positions of helix H12 in two GEN-ERβ complexes in the presence (blue, PDB code 1X7J) and absence (green, PDB code 1QKM) of a coactivator fragment. d Superposition of ERα LBPs in complex with PhIP (yellow, PDB code 2QXM) and 4-OH-PhIP (pink, PDB code 2QSE). Residues involved in PhIP and 4-OH-PhIP binding are colored in yellow and pink, respectively. e Superposition of ERα LBPs in complex with PhIP (blue, PDB code 2QXM) and E2 (yellow, PDB code 1GWR), respectively. f Superposition of ERβ and ERα LBPs in complex with GEN (blue, PDB code 1X7J) and DES (green, PDB code 3ERD), respectively. Residues involved in GEN and DES binding are colored in blue and green, respectively. W Water molecule. Helix and residue numbers are indicated

Fig. 4

Structural determinants of ligand recognition by ERRs. a Overall structure of unliganded ERRγ LBD (PDB code 1KV6) in cartoon representation. The unoccupied LBP is highlighted in black. b Superposition of ERRγ LBPs in absence of ligand (yellow, PDB code 1KV6) and in complex with BPA (green, PDB code 2E2R). Residues involved in BPA binding are colored in green and equivalent residues in the unliganded receptor are colored in yellow. c Superposition of ERRγ LBP in absence of ligand (yellow, PDB code 1KV6) and of the DES-bound form (blue, PDB code 1SP9). Residues involved in DES binding are colored in blue and equivalent residues in the unliganded receptor are colored in yellow

Fig. 5

Structural determinants of ligand recognition by PXR. a Close-up view of the flexible elements found specifically in PXR. They are inserted between helices H1 and H3 and comprise two-stranded antiparallel β-sheet (s1 and s1′), a disordered loop and two flexible loops. These elements are visible in the structure of unliganded PXR (green, PDB code 1ILG) whereas they are too disordered to be visible in the structure of PXR bound to rifampicin (purple, PDB code 1SKX). b The structure of PXR LBD in complex with hyperforin (PDB code 1M13) is rendered by thermal displacement parameters (B factor) ranging from blue (low) to red (high). c Close-up view of PXR LBP in complex with rifampicin (PDB code 1SKX). PXR residues involved in rifampicin binding are colored in purple and rifampicin is shown in yellow. d Close-up view of PXR LBP in complex with hyperforin (PDB code 1M13). PXR residues involved in hyperforin binding are colored in green and hyperforin is shown in yellow

Fig. 6

Structural determinants of ligand recognition by RXRs. a Close-up view of the 9-cis-RA binding pocket of RXRα (PDB code 1FBY). RXR residues involved in 9-cis-RA binding are colored in yellow and 9-cis-RA is shown in orange. b Superposition of RXRα and RXRβ LBPs in complex with 9-cis-RA (orange, PDB code 1FBY) and methoprene acid (violet, PDB code 1UHL), respectively. Residues involved in 9-cis-RA and methoprene acid binding are colored in yellow and pink, respectively. c Superposition of RXRα LBPs in complex with 9-cis-RA (orange, PDB code 1FBY) and TPT (blue, PDB code 3KWY). Residues involved in 9-cis-RA and TPT binding are colored in yellow and blue, respectively