Acquisition of a Single Crystal X-ray Diffraction System for Macromolecular and Small Molecule Crytsallography

用于大分子和小分子晶体学的单晶 X 射线衍射系统的获取

• 批准号: 10177052
• 负责人: Karen N. Allen
• 金额: $ 56.07万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10177052
• 关键词: 11 year old; Air; Anodes; Boston; Cartilage; Crystallization; Data Collection; Degenerative polyarthritis; Drug Delivery Systems; Exposure to; Funding; Future; General anesthetic drugs; Harvest; Head; Image; Immunologic Deficiency Syndromes; In Situ; Intervention; Life; Ligands; Macromolecular Complexes; Maintenance; Manuals; Mechanics; Medical; Minor; Molecular Structure; Muscle; Natural Products; Noise; Occupations; Oxidation-Reduction; Pathway interactions; Performance; Photons; Polysaccharides; Productivity; Property; Proteins; Regulation; Request for Proposals; Research; Research Personnel; Resolution; Rivers; Roentgen Rays; Running; Semiconductors; Services; Signal Transduction; Site; Source; Specimen; Speed; System; Therapeutic; Time; United States National Institutes of Health; Universities; Work; X ray diffraction analysis; base; data quality; detector; improved; instrument; protein protein interaction; sample collection; screening; small molecule; stereochemistry; tv watching

Abstract This proposal requests funds for the acquisition of a X-ray diffraction system that will meet the present and future on-site needs of a group of NIH-funded investigators located on the Charles River and Medical Campuses of Boston University. The proposed instrument will replace an eleven-year-old Bruker X8 Proteum-R diffractometer system which is reaching the end of its service life (no parts/service plan available after June 2020). We propose to purchase and install a new instrument featuring a reliable, low maintenance X-ray source and a state-of-the-art detector. Bruker’s IµS DIAMOND Cu source runs at low power and is air-cooled, yet the X-ray intensity surpasses the intensity of the existing rotating anode X-ray source. The proposed Photon III M28 CPAD detector will provide greatly improved sensitivity for weakly-diffracting samples and data collection at least five-fold faster via shutterless image acquisition capability. The new instrument will perform better for protein screening and data collection for macromolecular and small-molecule crystals. The vastly improved performance for small molecules based on faster screening time to identify target specimens will enable greater productivity through better data quality in terms of signal-to-noise, and enhanced speed of data collection. The fast data collection time allows determination of the connectivity and relative stereochemistry of small molecules with a speed rivaling that of NMR. The system will allow the determination of macromolecular structures and complexes with ligands and improve data quality of small or weakly diffracting crystals through use of the microfocus source and large-format detector, which allows for enhanced spatial resolution of the diffracted rays. Data collection will be optimized by utilizing the automated goniometer head to find the optimum crystal volume to expose, an impractical task using the coarse manual goniometer wrenches on the typical goniometer. The ISX plate-handling stage will allow in situ screening and data collection for mechanically sensitive crystals without harvesting from crystallization plates, and allow automated plate screening, maximizing users' work productivity for large screening jobs. These capabilities, which will afford improved throughput and data collection for samples that were previously unusable, will greatly support and enhance the NIH-funded projects of the five major and six minor users. The research topics include intervention in protein-protein interactions in immunodeficiencies; defining bacterial biosynthetic pathways; accelerating general anesthetic discovery; muscle regulation; redox regulation; natural products as therapeutics; synthesis of tunable organic semiconductors, and synthetic polysaccharides for drug delivery and to restore the properties of osteoarthritic cartilage.

摘要 该提案要求提供资金，用于购置一个X射线衍射系统， 目前和未来的现场需要一组NIH资助的调查人员位于查尔斯 波士顿大学的河流和医学校区。拟议的文书将取代 11年历史的布鲁克X8 Proteum-R衍射仪系统即将寿终正寝 使用寿命（2020年6月后无零件/服务计划）。我们建议购买并安装 一种新的仪器，具有可靠，低维护的X射线源和最先进的 检测器布鲁克公司的IµS DIAMOND Cu源以低功率运行，并采用空气冷却， 强度超过现有旋转阳极X射线源的强度。提议的光子 III M28 CPAD探测器将大大提高弱衍射样品的灵敏度， 通过无快门图像采集功能，数据采集速度至少提高五倍。新 仪器将更好地进行蛋白质筛选和大分子数据收集， 小分子晶体基于更快的速度，小分子的性能得到大幅提高 筛选时间，以确定目标标本将使更大的生产力，通过更好的数据 信噪比方面的质量，以及数据收集速度的提高。快速数据收集 时间允许测定小分子的连接性和相对立体化学， 其速度可与核磁共振相媲美。该系统将允许测定大分子 结构和配合物与配体和改善数据质量的小或弱衍射 通过使用微焦点源和大格式检测器来检测晶体，这允许 衍射射线的空间分辨率增强。数据收集将通过利用 自动测角器头找到最佳的晶体体积曝光，一个不切实际的任务 在典型的测角器上使用粗糙的手动测角器扳手。ISX印版处理 分级将允许对机械敏感晶体进行原位筛选和数据收集， 从结晶板收获，并允许自动化平板筛选，最大限度地提高用户的 大型筛选工作的工作效率。这些能力，将提供改进的 以前无法使用的样品的吞吐量和数据收集，将极大地支持和 加强NIH资助的五大六小用户项目。研究课题 包括干预免疫缺陷中蛋白质-蛋白质相互作用;定义细菌 生物合成途径;加速全身麻醉剂的发现;肌肉调节;氧化还原 调节;天然产物作为治疗剂;可调有机半导体的合成， 合成多糖用于药物递送和恢复骨关节炎软骨的特性。

项目成果

Unified, Asymmetric Total Synthesis of the Asnovolins and Related Spiromeroterpenoids: A Fragment Coupling Approach.

• DOI: 10.1021/jacs.2c05366
• 发表时间: 2022-07-20
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Yang, Feng;Porc, John A. o, Jr.
• 通讯作者: Porc, John A. o, Jr.