800 MHZ SPECTROMETER FOR BIOMOLECULAR NMR: CANCER

用于生物分子 NMR 的 800 MHZ 光谱仪：癌症

• 批准号: 7335092
• 负责人: Steven R Van Doren
• 金额: $ 16.5万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-15 至 2007-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7335092
• 关键词: DNA; ligands; neoplasm /cancer; proteins; university; urban area; zinc

This subproject is one of many research subprojects utilizing the resources provided by a Shared Instrumentation 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 grant, which is not necessarily the institution for the investigator. DESCRIPTION (provided by applicant): Seven groups of NMR users from the Columbia, St. Louis, and Kansas City campuses of the University of Missouri and from Washington University-St. Louis seek the first 800 MHz NMR spectrometer for the state of Missouri. The high field spectrometer will introduce structural biology of greater significance to their NIH projects. The University of Missouri-Columbia (UMC), in the geographical center of the life sciences corridor from St. Louis through Kansas City, will host the 800 MHz system. The advisory committee for deciding policy for the 800 will have broad representation from St. Louis to Kansas City. A fee system, uniformly applied among all users, will recover most of the operating costs of the 800. UMC offers a large matching package and new space tailored to hosting the 800 within a new building of its School of Medicine. The funds requested will be applied to an 800 MHz spectrometer with a shielded 18.8 T magnet. A cryogenic probe for outstanding sensitivity remains an additional high priority. The boosts in sensitivity, resolution, and TROSY line sharpening afforded by 800 MHz are needed by all these groups now using 600 MHz equipment. Four groups will employ the 800 for cancer-related work. The Van Doren group will investigate (i) interactions of metalloproteases with inhibitor and substrate proteins and (ii) interactions of transforming tumor viral proteins with their target proteins of host cells. Ma and Deutscher will determine NMR structures of galectin-3 bound to a tumor-targeting peptide and a full-length galectin-3 dimer. Ellen Li's group will investigate how ligands shift the equilibrium dynamics of retinoid-X-receptor (RXR) ligand binding domain. John-Stephen Taylor's group will obtain more detailed structural insights on DNA photoproducts underlying skin cancer. Henzl will study structural features and interactions of principal proteins (OCP2 and OCP1) in the auditory organ of the inner ear, a complex that binds connexin 26 most often mutated in hereditary deafness. Three groups will study DNA-binding protein assemblies. Dupureur's group will undertake the first NMR investigations of dynamics and conformational adjustments of a restriction endonuclease in response to DNA binding and conditions of "star activity". Laity will study structure and dynamics of the zinc-sensing DNA-binding domain of metal-responsive transcription factor-1 that regulates zinc homeostasis in mammals. He will study all six of its zinc fingers free and bound to DNA. Dreyfus and Laity will characterize the structure and dynamics of cytolethal CdtB toxin from pathogenic bacteria, free and bound to DNA. The CdtB subunit is sufficient to cause DNA damage and to arrest the cell cycle in mammalian cells.

该子项目是利用 NIH/NCRR 资助的共享仪器补助金提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是资助机构，不一定是研究者的机构。描述（由申请人提供）：来自密苏里大学哥伦比亚分校、圣路易斯分校和堪萨斯城分校以及华盛顿大学圣路易斯分校的七组 NMR 用户。 Louis 正在为密苏里州寻找第一台 800 MHz 核磁共振波谱仪。高场光谱仪将为其 NIH 项目引入具有更重要意义的结构生物学。密苏里哥伦比亚大学 (UMC) 位于从圣路易斯到堪萨斯城的生命科学走廊的地理中心，将托管 800 MHz 系统。为 800 人制定政策的咨询委员会将拥有从圣路易斯到堪萨斯城的广泛代表。对所有用户统一实施的收费系统将收回 800 的大部分运营成本。UMC 提供大型配套套餐和专为在其医学院新大楼内容纳 800 而定制的新空间。所申请的资金将用于配备 18.8 T 屏蔽磁体的 800 MHz 光谱仪。具有出色灵敏度的低温探头仍然是一个额外的优先事项。现在使用 600 MHz 设备的所有这些团体都需要 800 MHz 提供的灵敏度、分辨率和 TROSY 线锐化方面的提升。四个团体将雇用 800 人从事与癌症相关的工作。 Van Doren 小组将研究（i）金属蛋白酶与抑制剂和底物蛋白的相互作用，以及（ii）转化肿瘤病毒蛋白与其宿主细胞靶蛋白的相互作用。 Ma 和 Deutscher 将确定与肿瘤靶向肽和全长 galectin-3 二聚体结合的 galectin-3 的 NMR 结构。 Ellen Li 的团队将研究配体如何改变类维生素A-X-受体（RXR）配体结合域的平衡动力学。 John-Stephen Taylor 的团队将获得有关皮肤癌背后的 DNA 光产品的更详细的结构见解。 Henzl 将研究内耳听觉器官中主要蛋白质（OCP2 和 OCP1）的结构特征和相互作用，这是一种结合连接蛋白 26 的复合物，连接蛋白 26 在遗传性耳聋中最常发生突变。三个小组将研究 DNA 结合蛋白组装体。 Dupureur 的小组将首次对限制性核酸内切酶响应 DNA 结合和“星号活性”条件的动力学和构象调整进行核磁共振研究。 Laity 将研究金属响应转录因子 1 的锌敏感 DNA 结合域的结构和动力学，该转录因子调节哺乳动物体内的锌稳态。他将研究其所有六个游离和与 DNA 结合的锌指。 Dreyfus 和 Laity 将表征来自病原菌、游离的和与 DNA 结合的细胞致死 CdtB 毒素的结构和动力学。 CdtB 亚基足以引起 DNA 损伤并阻止哺乳动物细胞的细胞周期。