ORNAGOMETALLIC INHIBITORS FOR GLYCOGEN SYNTHASE KINASE 3BETA

糖原合成酶激酶 3BETA 的有机金属抑制剂

• 批准号: 7955541
• 负责人: DAVID W CHRISTIANSON
• 金额: $ 2.48万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7955541
• 关键词: Active Sites; Affinity; Anodes; Binding; Cells; Collaborations; Complex; Computer Retrieval of Information on Scientific Projects Database; Data Set; Development; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Funding; Generations; Glycogen Synthase Kinase 3; Glycogen Synthase Kinases; Grant; Housing; Image; Institution; Laboratories; Lead; Ligands; Metals; Mutation; Research; Research Personnel; Resolution; Resources; Roentgen Rays; Ruthenium; Side; Source; Structure; Time; United States National Institutes of Health; Work; X-Ray Crystallography; design; detector; glycogen synthase kinase 3 beta; improved; inhibitor/antagonist; interest; metal complex; mutant; three dimensional structure

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.

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。 我们的实验室专注于动力学惰性酶抑制剂的芳族复合物的发展。在这个概念中，金属中心控制有机配体的方向，以实现与酶活性位点相匹配的独特三维结构。具有结合的器官化合物的靶酶的X射线晶体学是这项工作的核心部分。 现在，我们对提高GSK-3的铅结构的亲和力和选择性特别感兴趣。负责金属配合物效力和选择性的活跃方面的功能组将通过在GSK-3的活跃部位引入突变来投资。这项工作将包括以下目的：与器官抑制剂获得天然和突变GSK-3BETA的共晶结构：这些结构将使我们能够详细了解结合模式并设计GSK-3的第二代抑制剂。我们已经与第一代化合物之一获得了共晶。这些晶体在内部X射线源没有衍射（R Axis IV ++图像板检测器安装在Rigaku-200 HB旋转阳极X射线发电机Christianson Lab上）。但是，我们能够在Chess F1Beamline（与David Christiansons博士合作）上收集完整的数据集。这些晶体衍射为3.1€，并确定了单位细胞参数。该提案的目的是要求光束时间收集从质量更高的晶体获得的高分辨率数据集。