Ho

Raloxifene

The inhibition of the ER by the triphenylethylene derivatives and by their cyclic analogs has been rationalized using the structures of their complexes with the receptor, as determined by X-ray diffraction data.12 The agonists and antagonists bind at the same site, but with different binding modes, as shown in Fig. 3.8. Recognition of estradiol by the ligand-binding domain of the receptor involves a combination of polar and nonpolar interactions. Thus, the A ring and the A/B interface interact with the side chains of Ala-350, Leu-387, and Phe-404, while the D ring contacts with Ile-424, Gly-521, and Leu-525. The hydroxyl at the phenolic ring of ring A establishes hydrogen bonds with the carboxylate of Glu-353, the guanidinium group of Arg-394 and a water molecule. The hydroxyl group at the C-17 position of the D ring establishes a hydrogen bond with the His-524 residue. The antagonists, exemplified by raloxifene, occupy the same binding sites but the interaction is different. The imidazole ring in the His-524 rotates in order to accommodate the difference in position of the hydroxyl group in raloxifen that corresponds to the hydroxyl at C-17 in estradiol. The rest of the interactions are similar in both cases, but the antagonists have additional hydrophobic interactions due to the side chain, and also a hydrogen bond between the basic group present in the side chain and the carboxylate group of Asp-351.

After binding of an agonist to the ligand-binding domain of the ER, a confor-mational change takes place on which the helix H12 is placed against the

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