Molecular basis of agonism and antagonism in the oestrogen receptor

Abstract

Oestrogens are involved in the growth, development and homeostasis of a number of tissues. The physiological effects of these steroids are mediated by a ligand-inducible nuclear transcription factor, the oestrogen receptor (ER). Hormone binding to the ligand-binding domain (LBD) of the ER initiates a series of molecular events culminating in the activation or repression of target genes. Transcriptional regulation arises from the direct interaction of the ER with components of the cellular transcription machinery. Here we report the crystal structures of the LBD of ER in complex with the endogenous oestrogen, 17beta-oestradiol, and the selective antagonist raloxifene, at resolutions of 3.1 and 2.6 A, respectively. The structures provide a molecular basis for the distinctive pharmacophore of the ER and its catholic binding properties. Agonist and antagonist bind at the same site within the core of the LBD but demonstrate different binding modes. In addition, each class of ligand induces a distinct conformation in the transactivation domain of the LBD, providing structural evidence of the mechanism of antagonism.

Antiestrogens: structure-activity relationships and use in breast cancer treatment

“…This interaction displaces H12 from its position in the binding groove observed in structures with 4-hydroxytamoxifen (OHT) and raloxifene (Fig. 2C) (Brzozowski et al . 1997, Shiau et al .…”

“…The ligand-binding pocket is formed within the hydrophobic core of the LBD below the central layer of helices (Fig. 2B) and is lined by hydrophobic residues from H3, H6, H8, H11, H12 and the S1/S2 hairpin (Brzozowski et al . 1997).…”

“…Agonist (E2) binding stabilizes a conformation of the ligand-binding domain where H12 folds tightly back on top of the ligand-binding pocket (Fig. 2B), positioning a set of amino acids (Asp538, Leu539, Glu542 and Met543) adequately for coactivator peptide interaction (Brzozowski et al . 1997, Shiau et al .…”

“…Crystallographic studies have revealed that the tertiary amine of raloxifene forms a hydrogen bond with Asp351 in H3 of the ERα LBD (Fig. 3) (Brzozowski et al . 1997).…”

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Figure 3Role of Asp351 in the different activity of tamoxifen and raloxifene. Overlay of X-ray structures of 4-hydroxytamoxifen (green) and raloxifene (aqua) bound to ERα (data from Shiau et al (1998) and Brzozowski et al (1997), respectively). The distance from Asp351 to the dimethylamine in 4-hydroxytamoxifen (3.8 Å) is 1.0 Å longer than to the piperidine in raloxifene.

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