STRUCTURAL STUDIES OF THE HUMAN ESTROGEN RECEPTOR(HER): HER MUTANTS, HER COMP

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The proposed project is part of our ongoing efforts to structurally characterize the human Estrogen Receptor (hER) and evaluate synthetic modulators of its activity for therapeutic purposes. In the past we have collected data at the APS on several complexes of the hER ligand binding domain (LBD) with novel ligands with unusual structural scaffolds that have variable efficacy on the two isoforms of hER. Under this new proposal, we will collect data on crystals of a series of hER deletion mutants encompassing its different domains. Here our emphasis is on the structural characterization of the hER protein in its entirety. To date, the only known structures of ER are those of its individual LBD and DBD (DNA binding domain). In addition, we will also characterize the crystal complexes of hER LBD and its various co-activator protein partners. In the past, we worked mostly with ERalpha but have since obtained crystals of ERbeta LBD in complex with various ligands as well as with other proteins. We have also initiated efforts on crystallizing other nuclear receptors including the Glucocorticoid receptor and novel orphan receptors with no known ligands. We have crystallized several of the above-mentioned proteins and are currently in the process of screening different crystal forms for diffraction quality and optimizing their growth conditions.