National HTX Center: Enabling Access to State-of-the-Art Crystallization Capabilities

国家 HTX 中心：获得最先进的结晶能力

• 批准号: 10193844
• 负责人: Sarah Elizabeth Johnson Bowman
• 金额: $ 109.26万
• 依托单位: HAUPTMAN-WOODWARD MEDICAL RESEARCH INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10193844
• 关键词: Address; Architecture; Area; Biological; Chemicals; Communities; Computer software; Computers and Advanced Instrumentation; Coupled; Crystallization; Crystallography; Deposition; Development; Disease; Ensure; Equipment; Funding; Goals; Government; Growth; Health; Image; Image Analysis; Imaging technology; Infrastructure; Institutes; Laboratories; Link; Liquid substance; Medical Research; Metadata; Methods; Molecular Structure; National Institute of General Medical Sciences; Outcome; Process; Protocols documentation; Research; Research Institute; Research Personnel; Resources; Robotics; Roentgen Rays; Sampling; Science; Services; Source; Structure; System; Technology; United States National Institutes of Health; X ray diffraction analysis; X-Ray Crystallography; analysis pipeline; beamline; computer infrastructure; computerized tools; cost; crystallinity; design; detector; drug development; experimental study; flexibility; high throughput screening; image processing; improved; innovation; insight; instrument; instrumentation; macromolecule; operation; outreach; protein data bank; repository; scale up; screening; screening services; structural biology; success; tool

PROJECT SUMMARY Structural biology is a field with a goal to delineate the physical architecture of biological macromolecules; a primary structural method employed in this endeavor is macromolecular X- ray crystallography (MX). MX methods account for nearly 90% of the greater than 165,000 structures deposited to the Protein Data Bank, but a primary challenge to successful MX structure determination is finding conditions in which a macromolecule will crystallize. To address this obstacle, an arsenal of chemical cocktail screens and high-throughput screening methods, coupled with specialized imaging, have been brought to bear on the problem of determining the conditions in which a macromolecular target will form a crystal that is of sufficient quality to be amenable to X-ray diffraction structure determination. This proposal focuses on continuing and extending the capabilities of a central resource providing critical high-throughput crystallization screening to the scientific community, the High-Throughput Crystallization Screening Center (HTX) at Hauptman-Woodward Medical Research Institute. The HTX Center has been in operation for two decades, providing a unique national crystallization resource specifically geared to help overcome the obstacle of coaxing a macromolecule to crystallize. The HTX Center provides a high-throughput screening format designed to minimize sample requirements via use of small volume liquid-handling robotics, a unique experimental set-up, and state-of-the-art imaging for screening. Notably, the technologies, instruments, and expertise available at the HTX Center are not widely available. This proposal focuses on extending the capabilities of the HTX Center by developing an expanded repertoire of experimental screening options and improved image analysis and processing, while performing instrumentation upgrades to maintain the HTX Center as a premier resource for crystallization screening for the scientific user community. We propose developing and implementing the necessary computational infrastructure and software to accommodate new screening plate definitions and optimization of successful crystallization hits, and improved user interfaces to maximize the information accessibility from screening experiment outcomes. A major goal of this proposal is to increase access to the state-of-the-art crystallization screening instrumentation and expertise to researchers from a wide array of laboratories in academic, non-profit and government institutes, with an objective to ensure access that enables a broad range of biomedically important research.

项目概要 结构生物学是一个目标是描绘生物的物理结构的领域 大分子；这项工作中采用的主要结构方法是大分子 X- 射线晶体学（MX）。 MX 方法占 165,000 多个方法中的近 90% 结构存入蛋白质数据库，但成功 MX 结构的主要挑战 测定是寻找大分子结晶的条件。为了解决这个问题 障碍，化学鸡尾酒筛选和高通量筛选方法的武库， 加上专门的成像，已经解决了确定 大分子靶材形成具有足够质量的晶体的条件 适合X射线衍射结构测定。该提案的重点是继续和 扩展提供关键高通量结晶的中央资源的能力 科学界筛选，高通量结晶筛选中心 （HTX）在豪普特曼伍德沃德医学研究所。 HTX中心已在 经营二十年，提供独特的国家结晶资源 帮助克服诱导大分子结晶的障碍。 HTX 中心 提供高通量筛选形式，旨在通过使用最大限度地减少样品需求 小容量液体处理机器人、独特的实验装置和最先进的技术 用于筛查的成像。值得注意的是，HTX 提供的技术、仪器和专业知识 中心并不广泛可用。该提案的重点是扩展 HTX 的功能 中心通过开发扩展的实验筛选选项并改进 图像分析和处理，同时执行仪器升级以维持 HTX 该中心是科学用户群体结晶筛选的首要资源。我们 建议开发和实施必要的计算基础设施和软件 以适应新的筛选板定义和成功结晶的优化 点击率和改进的用户界面，以最大限度地提高筛选信息的可访问性 实验结果。该提案的一个主要目标是增加获得最先进技术的机会 为来自各个领域的研究人员提供结晶筛选仪器和专业知识 学术、非营利和政府机构的实验室，目的是确保访问 这使得广泛的生物医学重要研究成为可能。