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.

项目摘要 结构生物学是一个以描述生物的物理结构为目标的领域。 大分子;在这种奋进中采用的主要结构方法是大分子X- 射线晶体学（MX）。MX方法在大于165，000种中占近90% 结构存放到蛋白质数据库，但成功的MX结构的主要挑战 确定是找到一个大分子结晶的条件。为了解决这个 障碍，化学鸡尾酒筛选和高通量筛选方法的武库， 再加上专门的成像，已经被带到承担的问题，确定 大分子目标将形成晶体的条件，该晶体具有足够的质量， 适合于X射线衍射结构测定。该提案的重点是继续并 扩展中央资源的能力，提供关键的高通量结晶 筛选到科学界，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中心已经在 经营二十年，提供独特的民族结晶资源，专门面向 以帮助克服诱导大分子结晶的障碍。HTX中心 提供了一种高通量筛选格式，旨在通过使用 小体积液体处理机器人，独特的实验装置，以及最先进的 成像用于筛查。值得注意的是，HTX的技术、仪器和专业知识 中心并没有广泛使用。该提案的重点是扩展HTX的功能 中心通过开发一个扩大的剧目的实验筛选的选择和改善 图像分析和处理，同时进行仪器升级，以维护HTX 中心作为科学用户社区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 以适应新的筛板定义和成功结晶的优化 点击率，并改进用户界面，以最大限度地从筛选中获取信息 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， 结晶筛选仪器和专业知识的研究人员从广泛的阵列， 学术、非营利和政府机构的实验室，目的是确保获得 这使得广泛的生物医学重要研究成为可能。