NMR and Computational Studies of Biomolecules

描述（由申请人提供）：拟议研究的总体目标是授权核磁共振光谱用于表征大型和具有生物学意义的蛋白质和蛋白质复合物。这将导致对生物机制的新见解，并最终导致改善人类健康。蛋白质主要通过与其他蛋白质、核酸、小配体或底物相互作用而起作用。因此，这项资助的总体目标是了解基于结构见解的机制，重点是蛋白质相互作用。这将通过开发一套NMR方法来实现，这些方法可以表征50 kDa及以上范围内具有挑战性的蛋白质复合物。该提案的所有组成部分都包括技术发展和对在疾病中起作用的重要靶标的应用，这些靶标是潜在的药物靶标，或天然产物的生产者。第一部分（Wagner）是关于大蛋白质和蛋白质复合物结构表征的核磁共振方法。它将开发蛋白质和蛋白质复合物研究的新方法，并将这些方法用于表征病毒内部核糖体进入位点（IRES） RNA与翻译起始因子的相互作用。组分2 （Wagner/Walsh）位于肠obactin非核糖体肽合成酶上。它将求解该体系的大型多域单元的结构，并确定EntF和EntB之间的配合物的结构。组分3 （Reinherz）将阐明t细胞受体信号元件的结构和功能。组分4 （Naar）将研究病原菌多效耐药系统的结构和功能。该研究将由三个核心支持：管理（核心A），核磁共振仪器和化学（核心B）和计算（核心C）。该POI资助的研究组件和核心之间的相互作用模拟了许多新的核磁共振和数据处理技术的发展，这些技术现在促进了具有挑战性的大分子体系的结构研究。我们预计，拟议的研究将继续推进核磁共振结构生物学的能力。

DESCRIPTION (provided by applicant): The overall goal of the proposed research is to empower NMR spectroscopy for characterizing large and biologically significant proteins and protein complexes. This will lead to new insights into biological mechanisms and will ultimately lead to improving human health. Proteins function primarily by interacting with other proteins, nucleic acids, small ligands or substrates. Thus, the overall goal of this grant is to understand mechanism based on structural insights, with a focus on protein interactions. This will be achieved with developing a set of NMR methods that can characterize challenging protein complexes in the range of 50 kDa and beyond. All components of the proposal contain both technology developments and applications to important targets that play roles in disease, are potential drug targets, or producers of natural products. Component 1 (Wagner) is on NMR approaches for structural characterization of large proteins and protein complexes. It will develop new methods for studies of proteins and protein complexes and will apply these for characterizing interactions of a viral internal ribosome entry site (IRES) RNA with translation initiation factors. Component 2 (Wagner/Walsh) is on the Enterobactin non-ribosomal peptide synthetase. It will solve structures of large mufti-domain units of this system and determine structures of complexes between EntF and EntB. Component 3 (Reinherz) will elucidate the structure and function of the signaling elements of the T-cell receptor. Component 4 (Naar) will investigate the structure and function of the pleiotropic drug resistance system of pathogenic yeast. The research will be supported by three cores for Administration (Core A), NMR instrumentation and Chemistry (Core B) and Computation (Core C). The interaction between the research components and cores of this POI grant simulated the development of many new NMR and data processing techniques that now facilitate structural studies of challenging macromolecular systems. We anticipate that the proposed research will continue to advance the capabilities of NMR for structural biology.