High Flux X-ray Crystallography Data Collection System

描述(由申请人提供)： 这项提案要求提供资金，用于我们实验室的一些研究中用于生物大分子结构测定的X射线衍射数据采集系统，该系统由带聚焦镜的高强度旋转阳极X射线源、成像板探测器、低温冷却附件和计算机组成。该仪器将服务于大分子结晶学家和他们的合作者社区，他们中的大多数人居住在弗吉尼亚联邦大学结构生物学和药物发现研究所。使用该仪器进行的结构研究都与广泛的基础、生物医学意义的项目相协调，利用生物化学家、分子生物学家、药物化学家以及结晶学家的技能。这些研究包括：脂肪酸生物合成和中间代谢酶，可作为结核病等疾病新药发现的靶点；磷酸吡哆醛和叶酸代谢酶，可作为新癌化疗药物和心血管治疗的潜在靶点；镰状细胞血红蛋白抗镰状病药的开发；蛇毒及其在纤溶、血栓形成和阿尔茨海默病中发挥关键作用的肝素和其他配体的复合体；RNA甲基酶，可用于感染性疾病的潜在药物靶点；以及致病细菌转录因子。大分子结构的测定是这些项目的重要组成部分，由6名经验丰富的X射线结晶学家组成的团队进行。请拨资金的仪器将取代已有15年历史的X射线衍射数据收集系统，该系统在整个期间一直持续大量使用，现在经常出现故障，导致结构确定工作的延误和需要这些结构的研究项目的中断。该仪器将安置在结构生物学和药物发现研究所内并进行维护，弗吉尼亚联邦大学对该研究所做出了提供基础设施和维护支持的长期承诺。

DESCRIPTION (provided by applicant): This proposal requests funds for an x-ray diffraction data collection system consisting of a high intensity rotating anode x-ray source with focusing mirrors, image plate detector, cryocooling accessory and computer to be used in biological macromolecule structure determination in a number of studies in our laboratories. This instrument will serve a community of macromolecule crystallographers and their collaborators, most of whom are housed in the Institute of Structural Biology and Drug Discovery of Virginia Commonwealth University. The structural studies to be carried out with this instrument are all coordinated with broad projects of basic, biomedical significance drawing on the skills of biochemists, molecular biologists and medicinal chemists as well as crystallographers. These studies include: enzymes of fatty acid biosynthesis and intermediary metabolism, which are targets for new drug discovery in such diseases as tuberculosis; enzymes of pyridoxal phosphate and folate metabolism that are potential targets for new cancer chemotherapeutic agents and cardiovascular treatment; development of anti-sickling agents for sickle cell hemoglobin; serpins and their complexes with heparin and other ligands, which play critical roles in fibrinolysis, thrombosis and Alzheimer's disease; RNA methylases, which are new potential drug targets in infectious diseases; and pathogenic bacterial transcriptional factors. The determination of macromolecule structures is an essential component of these projects and is carried out by a team of 6 experienced x-ray crystallographers. The instrument for which funds are requested will replace a 15 year old x-ray diffraction data collection system that has been in continuous and heavy use throughout that period and which is now suffering frequent failures with consequent delays in structure determination and disruptions of the research projects for which those structures are required. The instrument will be housed and maintained in the Institute of Structural Biology and Drug Discovery, to which Virginia Commonwealth University has made a long term commitment of provision of infrastructure and maintenance support.