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. Structure of the human Estrogen Receptor Alpha (ERa) ligand-binding domain (LBD) Bound to A Family of Compounds with an Oxabicyclic Phenol Scaffold. We are working to determine the structures of ERa LBD complexed with a series of oxabicyclic phenol compounds in order to understand how their structures relate to their biological activity. Our interest in these structures is part of our structure-function characterization of the two known ER subtypes, ERa and ER Beta (ERb). We have previously determined structures of ER LBD complexes with various ligands that can act as full estrogen agonists, partial agonists/antagonists, or complete antagonists, depending on the tissue and target gene promoter context Our interest in the compounds with the oxabicyclic phenol scaffold stems from our discovery that they are ERb-selective partial agonists in our cell based transcriptional assays. We have very recently determined the structure of ERa in complex with one member of this family, OBCP (4-[5-(hydroxymethyl)-6,8,9-trimethyl-3-oxabicyclo[3.3.1]non-7-en-2-yl]phenol). We have several related compounds that differ from OBCP in that they contain, one or two, instead of three methyl groups in the core oxabicyclic scaffold. These compounds vary in their potency and selectivity for ERa and ERb. However, as the methyl groups do not appear to directly participate in binding key residues within the ER ligand binding pocket, it is unclear how they differ in their ability to promote ER agonism. Also, it is unclear how they are partial agonists of ERb. An improved understanding of how this family of compounds binds to ER will allow us to better use this scaffold for the development of improved subtype selective agonists and/or novel antagonists.
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