Versatility or promiscuity: the estrogen receptors, control of ligand selectivity and an update on subtype selective ligands

Abstract

The estrogen receptors (ERs) are a group of versatile receptors. They regulate an enormity of processes starting in early life and continuing through sexual reproduction, development, and end of life. This review provides a background and structural perspective for the ERs as part of the nuclear receptor superfamily and discusses the ER versatility and promiscuity. The wide repertoire of ER actions is mediated mostly through ligand-activated transcription factors and many DNA response elements in most tissues and organs. Their versatility, however, comes with the drawback of promiscuous interactions with structurally diverse exogenous chemicals with potential for a wide range of adverse health outcomes. Even when interacting with endogenous hormones, ER actions can have adverse effects in disease progression. Finally, how nature controls ER specificity and how the subtle differences in receptor subtypes are exploited in pharmaceutical design to achieve binding specificity and subtype selectivity for desired biological response are discussed. The intent of this review is to complement the large body of literature with emphasis on most recent developments in selective ER ligands.

Figure 1

Taxonomy of the nuclear receptor (NR) superfamily and members of the families 1-6 (NR1-6).

Figure 2

17β-estradiol (E2) bound to ERα (yellow) and ERβ (blue). Only two residues, i.e., L384/M336 and M421/I373 (Erα/ERβ), differ in the binding pockets of ERα and ERβ. Unsurprisingly, the E2 binds in the subtypes in only subtlely different manners.

Figure 3

Domains A-F of ERα and ERβ, each playing a different structural/functional role. The numbers above the bars denote the residue numbers in the two receptor subtypes. ERα is slightly larger than ERβ, with a total of 595 amino acids (66 kDa) compared to 530 amino acids (59 kDa) for ERβ.

Figure 4

General architecture of an ER LBD comprising twelve α-helices and a beta sheet/hairpin. The twelve α-helices (H1 to H12) that form the “three-layered anti-parallel α helical sandwich” are colored differently for clarity (a). The conformation of an active ER (PDB ID: 1GWR) (b). The conformation of an inactive ER (PDB ID: 3ERT) (c). The major difference between b and c lies in the H12 conformation, highlighted in red.

Figure 5

Structures of natural estrogens: estradiol (E2, the most potent), estrone (E1) and estriol (E3). The four rings of the endogenous ligand, E2, are labelled A-D according to the widely accepted naming convention.

Figure 6

The diverse structures of ER-binding ligands. Most notably, these ligands contain at least an aromatic ring, a feature believed to confer the ability to bind the ERs.

Figure 7

Other endogenous ligands of the ERs, 5α-androstene-3β,17β-diol (adiol) and 27-hydroxycholesterol (27OH).

Figure 8

The binding of E2 in the pocket of ERα (PDB ID: 1GWR, yellow) and ERβ (PDB ID: 3OLL, blue), which are more or less comparable in size and volume. The phenolic A ring binds tightly to the pocket forming a triumvirate hydrogen bond network with a crystallographic water (red sphere), E353/305 (ERα/ERβ) and R294/246(ERα/ERβ) while the D ring forms a single hyrdrogen bond with H524/475 (ERα/ERβ). Apart from the A ring, the rest of the E2 molecule possesses high conformational flexibility.

Figure 9

Analogues of ERβ selective compound 10.

Figure 10

The non-steroidal AC-131 was used as the template in a SAR study to produce analogues such as compound 13 that showed ERβ selectivity. The feature that led to the ERβ selectivity for 8β-VE was repulsion from unfavorable interaction with M336 in ERβ, and for SERM-β1 was favorable hydrophobic contact with I373 in ERβ).