STRUCTURES OF RIBONUCLEOTIDE REDUCTASE

核糖核苷酸还原酶的结构

• 批准号: 8361673
• 负责人: Chris G Dealwis
• 金额: $ 4.39万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8361673
• 关键词: Allosteric Site; Binding; Catalysis; Catalytic Domain; Complex; DNA biosynthesis; Data; Free Radicals; Funding; Grant; Housing; Human; Libraries; National Center for Research Resources; Pharmaceutical Preparations; Play; Principal Investigator; RRM1 gene; Research; Research Infrastructure; Resolution; Resources; Ribonucleotide Reductase; Role; Source; Structure; United States National Institutes of Health; Viral Cancer; Yeasts; cost; dimer; inhibitor/antagonist; peptidomimetics; ribonucleotide reductase M2; structural biology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Ribonucleotide reductase (RR) catalyzes the rate-limiting step of de novo DNA synthesis by reducing NDPs to dNDPs. RR composes of a large catalytic ¿ subunit that houses the catalytic site and two allosteric sites, and a ¿ subunit that houses a free-radical that must be delivered to the catalytic site to initiate catalysis. Recent data show that the active eukaryotic RR1 is hexameric, hence departing from a previously held view of active RR1 dimers. ATP activates RR by inducing RR1 hexamers, while dATP inactivates RR by also inducing RR1 hexamers. One of the key questions that still remain to be answered is how can ATP be an activator while dATP an inhibitor if both effectors induce hexamerization of RR1? Due to the crucial role played by RR in dNTP synthesis, it is targeted for anti-cancer and viral therapy. In the past, we were able to determine the first eukaryotic RR1 structure from yeast (Xu et al., 2006A and 2006B PNAS) and recently the human RR1 (Fairman NSMB, 2010). During this proposal we will solve several structures of hRR1-drug complexes. We have also solved the first dATP-bound RR1 hexamer from yeast, albeit at 6 ¿ resolution. We wish to extend the resolution in order to understand why it is required for dATP to form RR1 hexamers to inactivate RR. In contrast ATP also forms RR1 hexamers and act as an activator of RR. We wish to determine the RR1-ATP hexamer structure to understand the mechanism of RR activation. We have shown that the C-terminus of the small subunit called RR2 can block RR assembly. We will solve structures of RR1 complexed with peptidomimetic libraries that block RR1-RR2 association.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 核糖核苷酸还原（RR）通过将NDP还原为DNDP来催化从头DNA合成的速率限制步骤。 RR组成的大型催化»载有催化位点和两个变构位点的亚基，以及一个容纳自由基的亚基，必须将其运送到催化部位以启动催化。最近的数据表明，活跃的真核RR1是六聚体，因此偏离了先前对活性RR1二聚体的视图。 ATP通过诱导的RR1六聚体激活RR，而DATP也通过诱导RR1六聚体灭活RR。仍然有待回答的关键问题之一是，如果两种效果诱导RR1的六聚体，ATP如何成为激活因子，而DATP是抑制剂？由于RR在DNTP合成中所起的至关重要的作用，因此它针对抗癌和病毒疗法。过去，我们能够确定酵母（Xu等，2006a和2006b PNA）的第一个真核RR1结构，以及最近的人类RR1（Fairman NSMB，2010年）。在此提案中，我们将解决HRR1-rug复合物的几个结构。我们还从酵母中解决了第一个DatP结合的RR1六聚体，尽管以6»分辨率。我们希望扩展该分辨率，以了解为什么DATP需要形成RR1六聚体以使RR灭活的原因。相反，ATP还形成RR1六聚体并充当RR的激活剂。我们希望确定RR1-ATP六聚体结构，以了解RR激活的机制。我们已经表明，称为RR2的小亚基的C末端可以阻止RR组件。我们将求解与阻断RR1-RR2关联的肽型图库的RR1结构。