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NMR STUDIES OF BIOLOGICALLY IMPORTANT OLIGOSACCHARIDES

具有重要生物学意义的低聚糖的核磁共振研究

基本信息

批准号：
6699327
负责人：
ANTHONY STEPHEN SERIANNI
金额：
$ 22.87万
依托单位：
UNIVERSITY OF NOTRE DAME
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-02-01 至 2006-01-31
项目状态：
已结题

项目摘要

Description: (From the applicant's abstract) Oligosaccharides are of central importance in the development and maintenance of biological systems. They are found free in solution, as constituents of glycoproteins and glycolipids on the cell surface, and have been implicated in the mechanisms of action of diverse cellular processes such as inflammation, cell-cell recognition and adhesion, protein turnover, and bacterial infection. Oligosaccharides, or molecular mimics thereof, are becoming more frequent targets in drug design for the treatment of human illness and disease. The cellular functions of oligosaccharides are intimately related to their three-dimensional shapes or conformations, and knowledge of these 3D structures, both free in solution and in the bound state, is essential to deciphering the underlying factors that control recognition between oligosaccharides and specific cellular receptors. This proposal aims to develop new probes of oligosaccharide conformation based on NMR parameters involving 13C and 2H. Major objectives are to fully establish the structural dependencies of JCH and JCC scalar couplings using experimental and computational methods, and to apply these couplings to investigate O-glycoside linkage conformation in the range of biologically important 13C-labeled di-, tri-, and tetrasaccharides, either free in solution or tethered to oligopeptides. Scalar couplings involving 15N will also be studied. Residual 13C-1H and 13C-13C dipolar couplings and residual 2H quadrupolar couplings in oriented media, and 13C chemical shift anisotropy, will be investigated as additional conformational constraints in solution. Motional properties will be investigated using molecular dynamics methods and these data compared to experimental data in order to assist in the interpretation of the latter. Investigations will then be extended to larger, biologically relevant systems including a complex high-mannose N-glycan found on CD2, engineered N-glycans on IgG, and DNA aptamer-oligosaccharide complexes.

描述：（来自申请人的摘要）低聚糖是人体的核心在生物系统的开发和维护中具有重要意义。他们是在溶液中游离存在，作为糖蛋白和糖脂的成分细胞表面，并与多种作用机制有关细胞过程，例如炎症、细胞间识别和粘附，蛋白质周转和细菌感染。寡糖，或分子其模拟物正在成为药物设计中更常见的目标治疗人类疾病。的细胞功能寡糖与其三维形状密切相关这些 3D 结构的构象和知识，在解决方案中都是免费的，在束缚态下，对于破译潜在的因素至关重要控制寡糖和特定细胞受体之间的识别。该提案旨在开发基于寡糖构象的新探针涉及 13C 和 2H 的 NMR 参数。主要目标是全面建立使用实验的 JCH 和 JCC 标量耦合的结构依赖性和计算方法，并应用这些耦合来研究 O-糖苷键构象在生物学上重要的范围内 13C 标记的二糖、三糖和四糖，游离在溶液中或与寡肽相连。涉及 15N 的标量耦合也将被研究。残余 13C-1H 和 13C-13C 双极耦合和残余 2H 四极定向介质中的耦合和 13C 化学位移各向异性，将作为解决方案中的额外构象限制进行研究。动感的将使用分子动力学方法和这些数据来研究特性与实验数据进行比较，以帮助解释后者。然后调查将扩展到更大的、生物学相关的系统包括在 CD2 上发现的复杂高甘露糖 N-聚糖，经过工程设计 IgG 上的 N-聚糖和 DNA 适体-寡糖复合物。