NMR spectroscopy instrumentation for probing intermolecular interations

描述(申请人提供)：用于探测分子间相互作用的核磁共振波谱仪器溶液中的核磁共振波谱已发展成为确定蛋白质和核酸结构的强大技术。最近，已经开发了一些基于核磁共振的方法来监测和表征分子间的相互作用。与其他技术相比，这些方法提供了独特的优势，并在结构生物学、化学生物学甚至药物发现中发挥了作用。差示标记的使用和TROSY类型技术的出现为核磁共振在结构生物学领域识别和表征大分子界面提供了额外的维度。此外，核磁共振还在研究和表征有机小分子与大分子靶标之间的相互作用方面发挥了重要作用，特别是在铅的识别和优化过程中。最近，我们成功地利用这些技术来表征分子间的界面，并随后指导高亲和力小分子结合剂的设计。在化学和生物的交界处，溶液核磁共振波谱的这些应用可以及早识别大分子络合物之间的关键相互作用位点，从而在没有络合物的原子分辨X射线结构的情况下提供关于可能的靶点的快速信息。在扩大我们目前在这些研究领域的独特能力和专业知识的基础上，我们请求提供资金，用于配备附件以实现更高信噪比的700 MHz仪器(低温探头)和实验室自动化(液体处理机和样品转换器)。所要求的仪器将部分服务于我们的圣地亚哥化学基因组学中心，以便向整个科学界提供，并将支持癌症细胞信号通路和传染病宿主-病原体相互作用领域的三个主要多组件项目。

DESCRIPTION (provided by applicant): Nuclear magnetic resonance spectroscopy instrumentation for probing intermolecular interactions Nuclear magnetic resonance spectroscopy in solution has evolved into a powerful technique for structure determination of proteins and nucleic acids. More recently, a number of NMR-based approaches have been developed to monitor and characterize intermolecular interactions. These approaches offer unique advantages over other techniques and find their utility in structural biology, chemical biology and even drug discovery. The use of differential labeling and the advent of TROSY-type techniques have provided an additional dimension to the use of NMR in the structural biology field in the identification and characterization of macromolecular interfaces. Moreover, NMR has also found an important role in the study and characterization of the interactions between small organic molecules and macromolecular targets, particularly useful in lead identification and optimization processes. We have recently successfully employed these techniques to characterize intermolecular interfaces and to subsequently guide the design of high affinity small molecule binders. At the interface between chemistry and biology, these applications of solution NMR spectroscopy allow early identification of key interaction sites between macromolecular complexes therefore providing rapid information on possible targeting sites in absence of atomic resolution X- ray structures of the complex. Expanding on our current unique capabilities and expertise in these areas of research, we request funds for a 700 MHz instrument equipped with accessories for a higher signal-to-noise ratio (cryoprobe) and laboratory automation (liquid handler and sample changer). The requested instrument will serve in part our San Diego Chemical Genomics Center, so that it would be available to the entire scientific community, and will also support three major multi- component projects in the areas of cell signaling pathways in cancer and host-pathogen interactions in infectious diseases.