Acquisition of a 900 MHz NMR Spectrometer

描述：我们建议购买一台900 MHz核磁共振波谱仪，并将其作为国家用户设施进行操作。计划中的科学实验包括溶液核磁共振和高分辨率固体核磁共振。 解决方案核磁共振：解决方案实验针对的是结构问题：达到或超过现有仪器的能力。我们强调样品制备技术的重要性，使我们能够研究最重要的生物学问题，而不仅仅是行为良好的模型系统。因此，我们的大多数分子还代表着抗癌、病毒感染、细菌和免疫疾病药物开发的靶标。我们的新型蛋白质表达策略使我们能够克服我们正在进行的几乎所有项目中的大多数溶解性和稳定性差的问题，因此确定溶液结构的极限障碍正从样品制备重新转移到光谱分辨率和灵敏度。我们的溶液核磁共振研究将包括大的蛋白质-蛋白质和蛋白质-核酸复合体的结构，以及成员C蛋白质的结构。高场光谱仪也将被用来表征蛋白质-配体复合体的特性，用于抗癌、病毒感染和免疫抑制的药物。我们将寻求更大的结构与R和结晶学，以受益于这两种技术的协同。 固体核磁共振：S的固态实验将利用一种新的偶极重新耦合技术，这种技术已经产生了小分子的初始从头结构。我们将把这些技术扩展到微晶蛋白质。此外，这些方法将使我们能够解决细菌视紫红质中H泵的机制问题，并开发出进行膜蛋白结构研究的方法。气泡的从头结构将从这些研究中显现出来。第二个感兴趣的领域是淀粉样纤维的结构，我们计划在其中确定与阿尔茨海默病相关的A蛋白的结构，以及与帕金森病相关的形成SH-3结构域和a-突触核蛋白的纤维。最后，高场将允许我们开发17O核磁共振作为研究生物系统的重要新工具。

DESCRIPTION: We propose to purchase a 900 MHz NMR spectrometer and operate it as a national user facility. The scientific experiments planned involve solution NMR and high-resolution solid state NMR. Solution NMR: the solution experiments are directed at structural problems that: are at or beyond the capabilities of presently available instrumentation. We emphasize the importance of sample preparation technologies that enable us to study the most significant biological problems rather than just well behaved model systems. Thus, most of our molecule also represent targets for development of drugs against cancer, viral infection, bacterial and immune diseases Our novel protein expression strategies have allowed us to overcome most of the problems of poor solubility and stability for nearly all projects we are working on so that the limiting hurdle of solution structure determination is shifting back from sample preparation to spectral resolution and sensitivity. Our solution NMR studies will include structures of large protein-protein and protein-nucleic acid complexes, and structures of member C proteins. The high-field spectrometer will also be utilized, to characterize protein-ligand complexes in the sear h for agents against cancer, viral infection and as immuno-suppressants. We will pursue larger structures with R and crystallography to benefit from the synergy of both techniques. Solid State NMR: S lid-state experiments will utilize a new class of dipolar recoupling techniques that have produced the initial de novo structure of a small molecule. We will extend these techniques to microcrystalline proteins. Further, the methods will permits us to address questions of the mechanism of H+ pumping in bacteriorhodopsin and to develop methods to perform structural studies of membrane proteins. The de novo structure of gas vesicles will emerge from these investigations. A second area of interest is the structure of amyloid fibrils where e plan to determine the structure of the A protein associated with Alzheimer's disease, as well as a fibril forming SH-3 domain and a-synuclein associated with Parkinson's disease. Finally, high fields will permit us to develop 17 O NMR as an important new tool for studies of biological systems.