| Estrogen receptor alpha (ERalpha) is an important therapeutic target for the treatment and prevention of hormone-dependent breast cancers. Tamoxifen is effective for the prevention and treatment of estrogen-dependent cancers while having beneficial effects on the bone and cardiovascular system. This compound belongs to the structurally diverse family of molecules known as selective estrogen receptor (ER) modulators (SERMs), which act as either estrogen agonists or antagonists in different environmental contexts. While tamoxifen becomes ineffective in advanced breast cancers and may increase the risk of uterine cancer, a structurally similar new compound GW5638 that has clinical potential exhibits no adverse effects on the uterus and shows considerable promise for treating breast cancer.; To understand the molecular and pharmacological basis of GW5638, we crystallized and solved the structure of the ERalpha ligand-binding domain (LBD) in complex with GW5638. Like tamoxifen, this compound relocates the carboxy-terminal helix (H12) to the known coactivator-docking site in the ERalpha LBD. However, GW5638 repositions residues in H12 through specific contacts with the N-terminus of this helix. In contrast to tamoxifen, the resulting increase in exposed hydrophobic surface of ERalpha LBD correlates with a significant destabilization of ERalpha in MCF-7 cells. Thus, the GW5638-ERalpha LBD structure reveals an unexpected mode of SERM-mediated ER antagonism, in which the stability of ERalpha is decreased through an altered position of H12.; GW5638 belongs to a class of molecules that has mixed functions (SERM/SERD). SERMs function either as agonists or antagonists, depending on the coregulator context. SERDs (selective estrogen receptor down-regulators) like ICI and ZK-703, act as more potent antagonists by inducing receptor turnover. This dual mechanism of antagonism may explain why GW5638 can inhibit tamoxifen-resistant breast tumors. |
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