New X-ray Diffractometer and Detector for Purdue Macromolecular Crystallography

用于普渡大学高分子晶体学的新型 X 射线衍射仪和探测器

• 批准号: 10431439
• 负责人: John Tesmer
• 金额: $ 85.99万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10431439
• 关键词: Achievement; Aging; Anodes; Award; Biological; Biological Sciences; Biophysics; Collection; Coupled; Crystallization; Crystallography; Data; Data Collection; Development; Disease; Faculty; Foundations; Funding; Grant; Health; Home; Hybrids; Image; Institutes; Life; Light; Liquid substance; Malignant Neoplasms; Mission; Modernization; Molecular; Molecular Structure; National Research Service Awards; Nitrogen; Noise; Optics; Performance; Phase; Proteins; Research Personnel; Resolution; Roentgen Rays; Sampling; Scientist; Series; Signal Transduction; Synchrotrons; Techniques; Time; Training; Training Programs; Universities; Update; X-Ray Crystallography; austin; cost effective; detector; drug development; flexibility; imaging system; improved; innovation; insight; nervous system disorder; new therapeutic target; photon-counting detector; pre-doctoral; recruit; repaired; structural biology

Summary Macromolecular structure determination at atomic resolution via X-ray crystallography is arguably one of the greatest technical achievements in the life sciences over the last century. By shedding light on molecular mechanisms essential for life, the technique has dramatically deepened our understanding of health and disease and accelerated the development of drugs that are more selective, potent, and safe. The story of protein crystallography at Purdue began in 1964 with the recruitment of Michael Rossmann, a pioneer in the field. A formal biophysics training program was instituted in 1989 with an NRSA Institutional Predoctoral Training Grant, coinciding with the award of a multi-million dollar Markey Foundation grant, which provided funds for hiring additional faculty and the X-ray generators currently in the existing X-ray facility. Armed with excellent facilities and expert faculty dedicated to advancing molecular biophysics and the training of junior scientists, Purdue produced many successful investigators including Hao Wu (Harvard), Liang Tong (Columbia), Marvin Hackert (UT Austin), and Jack Johnson (Scripps). John Tesmer, the PI of this proposal, is likewise a Purdue trainee. Purdue has also served as an important hub for innovation in the field. For example, Dr. Rossmann and Dr. Janet Smith were key contributors to the techniques of molecular replacement and MAD phasing, respectively, which are now the two most commonly used phasing techniques world-wide. A new era in Purdue structural biology has begun. In 2009, the university opened Hockmeyer Hall of Structural Biology, a 30 million dollar facility and the new home of the Macromolecular Crystallography core. Purdue reaffirmed its commitment to structural biology by updating the core with the 2019 purchase of a RockImager Duo crystal hotel and imaging system, and an Oxford Cryosystems 800 Series liquid nitrogen cooler. A reboot of our T32 Molecular Biophysics Training Program (funded 2019-24) now supports 7 trainees per year (Tesmer PI). The specific aim of this proposal is to fulfill a critical need by replacing our aging ~30 year old X-ray generators, which can no longer be repaired, with a modern, reliable, and cost effective MicroMax-007 HF rotating anode generator coupled to a synchrotron quality, Dectris Eiger2 hybrid photon counting detector. The generator and its advanced optics will provide a brilliant, small 90 µm X-ray beam at the crystal, optimizing signal-to-noise for small samples. The large 155x163 mm detector will be ideal for weak reflections, with small 75 µm pixels to resolve closely spaced reflections. A 4- circle kappa goniometer will add flexibility in data collection. The new setup will improve X-ray flux >100-fold, and the detector sensitivity is about 10 times greater than imaging plates, thereby improving our overall performance by about three orders of magnitude and enabling the collection of superior diffraction data from even the most challenging crystals. The new configuration will greatly benefit the scientific and educational mission of at least 20 faculty by not only providing high resolution biological insights into their targets, but also accelerating the development of novel therapeutics targeting cancer and neurological disease.

概括 通过 X 射线晶体学以原子分辨率测定大分子结构可以说是其中之一 上个世纪生命科学领域最伟大的技术成就。通过阐明分子 该技术极大地加深了我们对健康和疾病的理解 并加速了选择性更强、更有效、更安全的药物的开发。蛋白质的故事 普渡大学的晶体学研究始于 1964 年，当时该领域的先驱迈克尔·罗斯曼 (Michael Rossmann) 被聘用。一个 正式的生物物理学培训计划于 1989 年设立，并获得 NRSA 机构博士前培训补助金， 恰逢马基基金会授予数百万美元赠款，该赠款为招聘提供资金 现有 X 射线设施中现有的额外人员和 X 射线发生器。配备优良的设施 和致力于推进分子生物物理学和初级科学家培训的专家教师，普渡大学 培养了许多成功的研究者，包括吴浩（哈佛大学）、梁通（哥伦比亚）、马文·哈克特（Marvin Hackert） （德克萨斯大学奥斯汀分校）和杰克·约翰逊（斯克里普斯）。该提案的 PI 约翰·泰斯默 (John Tesmer) 同样是普渡大学的实习生。 普渡大学也是该领域创新的重要中心。例如，罗斯曼博士和博士。 Janet Smith 分别是分子替代和 MAD 定相技术的关键贡献者， 这是目前世界范围内最常用的两种定相技术。普渡大学结构的新时代 生物学开始了。 2009 年，该大学开设了霍克梅尔结构生物学馆，这是一座耗资 3000 万美元的设施 以及高分子晶体学核心的新家。普渡大学重申其对结构性改革的承诺 通过 2019 年购买 RockImager Duo 水晶酒店和成像系统来更新核心， 和 Oxford Cryosystems 800 系列液氮冷却器。重启我们的 T32 分子生物物理学培训 该计划（2019-24 年资助）现在每年支持 7 名学员（Tesmer PI）。该提案的具体目标是 通过更换我们老化的约 30 年的 X 射线发生器（无法再修复）来满足关键需求 与同步加速器耦合的现代、可靠且具有成本效益的 MicroMax-007 高频旋转阳极发生器 质量，Dectris Eiger2 混合光子计数探测器。该发生器及其先进的光学器件将提供 晶体上的明亮、小型 90 µm X 射线束，优化小样品的信噪比。大号155x163 mm 探测器非常适合弱反射，具有 75 µm 小像素，可解析紧密间隔的反射。一个 4- 圆形卡帕测角仪将增加数据收集的灵活性。新装置将提高 X 射线通量 >100 倍， 探测器灵敏度大约是成像板的 10 倍，从而提高了我们的整体水平 性能提高约三个数量级，并能够从 即使是最具挑战性的晶体。新的配置将极大有利于科学和教育 至少 20 名教员的使命不仅是为其目标提供高分辨率的生物学见解，而且 加速针对癌症和神经系统疾病的新疗法的开发。