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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 拟议的项目是我们正在进行的努力的一部分，目的是从结构上表征人类雌激素受体(HER)，并为治疗目的评估其活性的合成调节剂。过去，我们在APS收集了HER配体结合域(LBD)与具有不寻常结构支架的新配体的几个络合物的数据，这些配体对HER的两种异构体具有不同的疗效。根据这项新的提议，我们将收集一系列Her缺失突变体的晶体数据，这些突变体包含其不同的结构域。这里我们的重点是整个HER蛋白的结构特征。到目前为止，已知的ER结构只有其单个LBD和DBD(DNA结合域)的结构。此外，我们还将表征HER LBD及其各种共激活蛋白伙伴的晶体复合体。在过去，我们主要使用ERpha，但后来获得了ERbeta LBD与各种配体以及其他蛋白质的络合物的晶体。我们还开始努力结晶其他核受体，包括糖皮质激素受体和未知配体的新型孤儿受体。我们已经结晶了上述几种蛋白质，目前正在筛选不同晶型的衍射质量，并优化它们的生长条件。

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.