Structural Determination of Certain Novel ER Complexes
Abstract
Tamoxifen is effective for the prevention and treatment of estrogen-dependent breast cancers, but is associated with an increased incidence of endometrial tumors. I have completed the specific aims in this proposal including structural, biochemical and functional characterizations of estrogen receptor alpha (ERalpha) in complex with GW5638. This compound has a similar chemical structure to tamoxifen, but possesses a different pharmacological profile and has therapeutic potential for advanced breast cancers. The crystal structure revealed that like tamoxifen, GW5638 relocates the carboxyl-terminal helix (Hi 2) 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 degradation of ERalpha in MCF-7 cells. Thus, the GW5638-ERalpha LBD structure reveals a unique mode of SERM-mediated ER antagonism, in which the stability of ERalpha is decreased through an altered position of H12.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2005
- Accession Number
- ADA446299
Entities
People
- Ye-ling Wu
Organizations
- University of Chicago