CATALYTIC MECHANISM AND INHIBITION OF GOLGI ALPHA-MANNOSIDASE II

高尔基体α-甘露糖苷酶II的催化机制和抑制作用

• 批准号: 7721296
• 负责人: DAVID ROSE
• 金额: $ 4.06万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7721296
• 关键词: Affinity; Alpha-mannosidase; Binding; Catalysis; Class; Complex; Computer Retrieval of Information on Scientific Projects Database; Data; Data Set; Distant; Enzyme Inhibition; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Family; Funding; Future; Golgi Apparatus; Grant; Hour; Hydrolase; Institution; Property; Research; Research Personnel; Resolution; Resources; Site; Source; Structure; Time; United States National Institutes of Health; base; design; glycosylation; high throughput screening; inhibitor/antagonist; interest; mannosyl-oligosaccharide 1,3-1,6-alpha-mannosidase; novel; small molecule libraries; synchrotron radiation

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. We previously determined the structure of the glycosylation enzyme alpha-mannosidase II, a glycosyl hydrolase of the Family 38 family targetted by potential anti-metastatic compounds. Largely with data from CHESS, we have been analyzing the atomic basis of catalysis and inhibition of the enzyme through structures of complexes with intermediates and several classes of inhibitors. Recently, we performed two high-throughput screens of chemical libraries looking for novel inhibitors of the enzyme. This resulted in 10-12 hits of varying affinity and properties. We are interested in examining how these bind to the structure. In particular, some may be non-competitive inhibitors and may occupy sites distant from the catalytic centre, which will be of interest for future inhibitor design. We would like to use synchrotron radiation for two promary reasons. Firstly, we can get a data set in minutes, rather than hours, which will let us quickly examine several of these complexes in a short time. Secondly, we can get almost atomic resolution (1.2-1.4A) data from these crystals at CHESS. This resolution can be critical in understanding conformational distortions and determining precise interatomic distances.

该副本是利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，这不一定是调查员的机构。 我们先前确定了糖基化酶α-甘露糖苷酶II的结构，α-甘露糖苷酶II，该家族的糖基水解酶38家族的糖基水解酶，该家族由潜在的抗激活化合物靶向。在很大程度上，通过国际象棋数据，我们一直在分析通过与中间体和几类抑制剂的复合物结构进行催化和抑制酶的原子基础。 最近，我们进行了两个高通量屏幕的化学文库，以寻找新型酶的抑制剂。这导致了10-12次的亲和力和特性。我们有兴趣检查它们如何与结构结合。特别是，有些可能是非竞争力抑制剂，并且可能占据远离催化中心的部位，这对于将来的抑制剂设计非常有意义。 我们想使用同步加速器辐射，原因有两个。首先，我们可以在几分钟而不是数小时内获得数据集，这将使我们在短时间内快速检查其中几个复合物。其次，我们可以从国际象棋的这些晶体中获得几乎原子分辨率（1.2-1.4a）数据。该分辨率对于理解构象失真和确定精确的原子间距离至关重要。