FIGURE 3.9 Conformational changes following the activation of the estrogen receptor and their inhibition by raloxifene.

ligand-binding cavity, projecting its inner, hydrophobic surface toward the ligand. The outer, charged surface, which is essential for the interaction of the receptor with coactivators, is left outside (Fig. 3.9A).13 The alignment of H12 over the cavity is prevented by the binding of antagonists, exemplified by raloxifene, because their side chain is too long to fit the binding cavity and protrudes from the pocket between H3 and H11, preventing the holding of the helix H12 and hence the transcriptional activation function of ER (Fig. 3.9B). This helix displacement seems to be a common feature of steroidal and nonsteroidal antiestrogens with a bulky side chain.

Some ER-positive breast tumors that also overexpress the peptide growth factor receptor ERBB2 (also known as HER2) and/or epidermal growth factor receptor EGFR (also known as HER1) are relatively resistant to hormonal therapy, especially when tamoxifen is employed.14

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