ORNAGOMETALLIC INHIBITORS FOR GLYCOGEN SYNTHASE KINASE 3BETA

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。 我们的实验室致力于开发作为动力惰性酶抑制剂的Ru络合物。在这个概念中，金属中心控制着有机配体的取向，以获得与酶活性部位相匹配的独特的三维结构。结合了有机钚化合物的靶酶的X射线结晶学是这项工作的中心部分。 我们现在特别感兴趣的是提高我们的先导结构对GSK-3的亲和力和选择性。通过在GSK-3的活性部位引入突变，将研究活性侧对金属络合物的效力和选择性负责的官能团。本工作将包括以下目标：获得天然和突变体GSK-3beta与有机钚抑制剂的共晶结构：这些结构将使我们能够详细了解GSK-3的结合模式，并设计第二代GSK-3抑制剂。我们已经获得了与第一代化合物之一的共晶。这些晶体在内部X射线源(安装在Rigaku-200HB旋转阳极X射线发生器上的R轴IV++图像板探测器，Christian Lab)上没有衍射。然而，我们能够在国际象棋F1波束线(与大卫·克里斯汀森博士实验室合作)收集到完整的数据集。晶体的衍射率高达3.1°，并测定了晶胞参数。这项提议的目的是要求光束时间来收集高分辨率数据集，这些数据集将从质量更好的晶体中获得。

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 laboratory focuses on the development of ruthenium complexes as kinetically inert enzyme inhibitors. In this concept, the metal center controls the orientation of the organic ligands to achieve unique three-dimensional structures that match the enzyme active site. X-ray crystallography of target enzymes with bound organoruthenium compounds are a central part of this effort. We are now especially interested in improving the affinity and selectivity of our lead structures for GSK-3. The functilnal groups in the active side that that are responsible for the potency and selectivity of the metal complexes will be investigated by introducing mutations in the active site of GSK-3. This work will include the following aim: Obtaining co-crystal structures of native and mutant GSK-3beta with the organoruthenium inhibitors: These structures will allow us to understand the binding mode in detail and to design second generation inhibitors for GSK-3. We already obtained cocrystals with one of the first generation compounds. These crystals did not diffract at the in-house X-Ray source (R axis IV++ image plate detector mounted on a Rigaku-200HB rotating anode X-ray generator, Christianson Lab). However, we were able to collect a complete data set at CHESS F1beamline (in collaboration with Dr. David Christiansons Lab). These crystals diffracted up to 3.1 ¿ and the unit cell parameters were determined. The purpose of this proposal is to request beam time to collect high-resolution data sets that will be obtained from crystals with better quality.