STRUCTURAL STUDIES OF HSP90 CHAPERONE-CLIENT INTERACTIONS

HSP90 伴侣-客户相互作用的结构研究

• 批准号: 8171520
• 负责人: DANIEL T GEWIRTH
• 金额: $ 0.71万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171520
• 关键词: Client; Complex; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Funding; GRP94; Grant; Growth and Development function; Heat-Shock Proteins 90; Home environment; Institution; Ligand Binding Domain; Ligands; Malignant Neoplasms; Molecular Chaperones; N-terminal; Nature; Play; Proteins; Research; Research Personnel; Resolution; Resources; Roentgen Rays; Role; Source; Specificity; Staging; Structure; Time; United States National Institutes of Health; cell growth; novel; protein degradation; small molecule; synchrotron radiation; therapeutic target

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. Hsp90 chaperones play central roles in the later stages of client protein maturation and, because these clients moderate key checkpoints in cellular growth and development, are recognized as significant cancer therapeutic targets. Questions at the forefront of the field currently center on the development of inhibitory ligands of high specificity, and the nature of the interaction between the chaperone and its client proteins and accessory factors. We are requesting beam time to study the interaction of the hsp90 family of molecular chaperones with novel small molecule inhibitory ligands and previously uncharacterized macromolecular partners. We have previously determined high resolution crystal structures of intact GRP94 (the endoplasmic recticulum Hsp90), as well as the N- terminal ligand binding domain. Crystals of the N-terminal domain in complex with inhibitory ligands typically diffract to better than 2 ¿ using synchrotron radiation. Crystals of the intact chaperone diffract to roughly 2.5 ¿ under favorable conditions. Complexes between the chaperone and macromolecular partners such as the Erad (ER associated degradation) protein are expected to diffract weakly and, because of their small size, are difficult to characterize using home X-ray sources. Our plan is to use CHESS beam time to 1) collect high resolution data from crystals of GRP94-Nterm plus inhibitory ligands, and 2) characterize and collect data from crystals of intact GRP94 in complex with the Erad protein.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 HSP90伴侣在客户蛋白成熟的后期阶段起着核心作用，并且由于这些客户在细胞生长和发育中的中等关键检查点被认为是重要的癌症治疗靶标。该领域的最前沿问题目前是高特异性抑制性配体的发展，以及伴侣蛋白与其客户蛋白和附属因素之间相互作用的性质。我们要求光束时间研究分子链烷的Hsp90家族与新型小分子抑制配体和以前未表征的大分子伴侣的相互作用。我们先前已经确定了完整GRP94（内质巧克力HSP90）的高分辨率晶体结构以及N末端配体结合域。与抑制性配体复合物中N末端结构域的晶体通常使用同步加速器辐射衍射，比2`衍射。在有利条件下，完整的伴侣衍射的晶体约为2.5。链酮和大分子伴侣（例如ERAD（ER相关降解）蛋白）之间的复合物预期会弱衍射，并且由于其尺寸很小，因此很难使用Home X射线源来表征。我们的计划是使用国际象棋束时间到1）从GRP94-NTerm Plus抑制配体晶体中收集高分辨率数据，以及2）表征和收集来自Intact Grp94晶体的数据，该数据与Erad蛋白质中的复合物中。