STRUCTURAL BASIS OF NUCLEAR HORMONE RECEPTOR LIGAND INTERACTIONS

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 我们的研究重点是蛋白质的核激素家族。 核激素受体蛋白是配体诱导的转录因子。 核激素受体参与多种人类疾病，包括癌症、肝病、肥胖症和糖尿病。 具体来说，我们正在研究雌激素受体α（ER α LBD）和过氧化物酶体增殖物激活受体γ（PPAR-gamma）的配体结合结构域。 我们的目标是更好地了解这些蛋白质的部分激动机制，以便进行基于结构的药物设计。 在实验上，我们希望表征几种与PPAR和ER结合的部分激动剂，通过X射线晶体学解决结构，剖析配体的原子水平相互作用，并比较和对比这些相互作用和诱导的变构与完全激动剂和拮抗剂。 为此，我们纯化了这些蛋白质，合成了几种部分激动剂，并形成了这些复合物的大晶体。

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. Our research focuses on the nuclear hormone family of proteins. Nuclear hormone receptor proteins are ligand inducible transcription factors. Nuclear hormone receptors are involved in several human diseases including cancer, liver disease, obesity, and diabetes. Specifically, we are working with the ligand binding domains of estrogen receptor alpha (ERalpha LBD) and peroxisome proliferator activated receptor gamma (PPAR-gamma). Our goal is to acquire a better understanding of the partial agonism mechanism of these proteins in order to carry out structure based drug design. Experimentally, we desire to characterize several partial agonists bound to PPAR and ER, solve the structures by x-ray crystallography, dissect the atomic level interactions of the ligands, and compare and contrast these interactions and induced allostery with full agonists and antagonists. To this end, we have purified these proteins, synthesized several partial agonists, and formed large crystals of these complexes.