STRUCTURAL STUDIES OF THE DNA-BINDING AND LIGAND-BINDING DOMAINS OF THE HUMAN

人类 DNA 结合和配体结合域的结构研究

• 批准号: 7601591
• 负责人: Shyamala Rajan
• 金额: $ 0.28万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7601591
• 关键词: Agonist; Binding; Biological; Complex; Computer Retrieval of Information on Scientific Projects Database; DNA Binding Domain; Data; Development; Estrogen Receptor alpha; Estrogen Receptor beta; Funding; Gene Targeting; Grant; Human; Institution; KLK3 gene; Ligand Binding Domain; Ligands; Proteins; Regulation; Research; Research Personnel; Resolution; Resources; Running; Solutions; Source; Structure; Testing; Tissues; United States National Institutes of Health; improved; mutant; novel; promoter; scaffold

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. Since Spring 2005 we collected structural data at the APS which related to ERalpha ligand-binding domain (LBD) complexed with novel ligands that vary in their potency and selectivity for ERalpha and ERbeta. From these data, we were able to speculate on a possible mode of binding of these compounds to ERb for which they are more selective in solution. These OBCP compounds with their novel 3D scaffolds are being evaluated for various applications since their biological effects from being full agonists, partial agonists/antagonists, or complete antagonists, depending on the tissue and target gene promoter context. We continue our structure-function characterization of the two known ER subtypes with crystal complexes of ERbeta LBD and the OBCP compounds. These structures will further our understanding of how to better use the OBCP scaffold for the development of improved subtype selective agonists and/or novel antagonists. Another important development is that we finally have diffraction quality crystals of an ERbeta truncation mutant that includes the DNA-binding domain (DBD), a hinge region and the following LBD. This promises to be a high resolution structure since it diffracted to 1.34A when we tested it just before the end of the previous run. This is an exciting construct because, to date, there are no available structures of ERalpha/beta that include both the DBD and LBD. Determining this structure will bring us closer to understanding the structure-function regulation of the entire ERbeta protein, a therapeutically important molecule with multiple domains.

这个子项目是许多研究子项目中的一个 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， 因此可以在其他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。 自2005年春季以来，我们在APS收集了与ER α配体结合结构域（LBD）相关的结构数据，这些结构域与新型配体复合，其对ER α和ER β的效力和选择性各不相同。从这些数据中，我们能够推测这些化合物与ERb结合的可能模式，它们在溶液中更具选择性。这些OBCP化合物及其新的3D支架正在评估各种应用，因为它们的生物学效应是完全激动剂，部分激动剂/拮抗剂，或完全拮抗剂，这取决于组织和靶基因启动子背景。 我们继续我们的结构-功能表征的两个已知的ER亚型与晶体复合物的ER β LBD和OBCP化合物。这些结构将进一步加深我们对如何更好地使用OBCP支架来开发改进的亚型选择性激动剂和/或新型拮抗剂的理解。 另一个重要的进展是，我们终于有了ER β截短突变体的衍射质量晶体，该突变体包括DNA结合结构域（DBD），铰链区和随后的LBD。这有望成为一个高分辨率的结构，因为当我们在前一次运行结束前测试它时，它衍射到1.34A。这是一个令人兴奋的结构，因为到目前为止，还没有包括DBD和LBD的ER α/β结构。确定这种结构将使我们更接近于理解整个ER β蛋白的结构-功能调节，ER β蛋白是一种具有多个结构域的治疗重要分子。