Structural Analysis of the Dimerization Domain of the Human Estrogen Receptor and a Peptide Inhibitor of Dimerization
Abstract
The human estrogen receptor (hER) is a therapeutic target in estrogen-responsive breast cancers. It has been shown that a 12 amino acid phosphotyrosyl peptide composed of the sequence surrounding tyrosine 537 of hER is an inhibitor of the hER function. Base on a hypothesis that hER contains a discreet binding domain for the phosphopeptide, this project proposes to determine the three-dimensional structure of the proposed domain. Based on previous binding assay data, we prepared a fragment of hER corresponding to residues 253-341. Characterization using fluorescence and nuclear magnetic resonance spectroscopy, we show that this hER fragment does not have a well-defined structure, even in the presence of the phosphopeptide. These results, together with recently determined crystal structures of the hER ligand binding domain and other mutation studies, indicate that the original hypothesis is incorrect. Our new experiments suggest that the phosphopeptide inhibits hER by binding to the ligand binding domain. Thus, the focus of this project has been shifted to identifying the binding site within the hER ligand binding domain and identifying critical interactions. Results from this project will provide insights into development of new hER inhibitors for treatment of estrogen-responsive breast cancers.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 1998
- Accession Number
- ADB241545
Entities
People
- Shohei Koide
Organizations
- University of Rochester