Structural insights into the mode of action of a pure antiestrogen

Background: Estrogens exert their effects on target tissues by binding to a nuclear transcription factor termed the estrogen receptor (ER). Previous s tructural studies have demonstrated that each class of ER ligand (agonist, partial agonist, and SERM antagonist) induces distinctive orientations in t he receptor's carboxy-terminal transactivation helix. The conformation of t his portion of the receptor determines whether ER can recruit and interact with the components of the transcriptional machinery, thereby facilitating target gene expression. Results: We have determined the structure of rat ERP ligand binding domain (LBD) in complex with the pure antiestrogen ICI 164,384 at 2.3 Angstrom res olution. The binding of this compound to the receptor completely abolishes the association between the transactivation helix (H12) and the rest of the LED. The structure reveals that the terminal portion of ICI's bulky side c hain substituent protrudes from the hormone binding pocket, binds along the coactivator recruitment site, and physically prevents H12 from adopting ei ther its characteristic agonist or AF2 antagonist orientation. Conclusions: The binding mode adopted by the pure antiestrogen is similar t o that seen for other ER antagonists. However, the size and resultant posit ioning of the ligand's side chain substituent produces a receptor conformat ion that is distinct from that adopted in the presence of other classes of ER ligands. The novel observation that binding of ICI results in the comple te destabilization of H12 provides some indications as to a possible mechan ism for pure receptor antagonism.