High Resolution Tools for Structural Biology

用于结构生物学的高分辨率工具

• 批准号: 1904577
• 负责人: Ryan Julian
• 金额: $ 47万
• 依托单位: University of California-Riverside
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1904577&HistoricalAwards=false
• 关键词: Resolution; Tools; Structural; Biology

With support from the Chemical Measurement and Imaging Program in the Division of Chemistry, Professor Ryan Julian and his group at the University of California - Riverside are developing methods to improve our ability to determine the structure of proteins - key actors in biology for diverse and important functions that include serving as factories for energy and communications within and among cells. The Julian lab is developing new methods that can reveal the distance between different parts of a protein molecule, providing high resolution structures which contribute to understanding how proteins function and how their function might be manipulated at a molecular level. The primary tool used is mass spectrometry - a rapid technique that can be used with minuscule amounts of sample. Enhanced capabilities for structure determination by mass spectrometry are accelerating our understanding of crucial biological actors. A diverse group of graduate and undergraduate students are carrying out this research and receiving valuable training that will prepare them to push the boundaries of science and technology forward in the future. Dr. Julian and his team are also engaged in outreach efforts targeting high school students from underrepresented groups. The Julian group is developing new approaches to determining high resolution protein structures using energy transfer and covalent crosslinking between specific residues in order to establish multiple, well-defined distance constraints that can be used in conjunction with calculations to yield atomically-defined gas-phase structures. The energy-transfer approach has several key advantages for determination of high resolution structure, including: 1) direct probing of protein substructure, allowing the determination of multiple distance constraints in a single protein; 2) use of native residues for the donor and acceptor, allowing for the installation of any required amino acids by standard site-directed mutagenesis; and 3) extremely selective photochemical cleavage of bonds affording high sensitivity and unambiguous interpretation of the results. Utilizing the speed and sensitivity of mass spectrometry, gas-phase structural biology can tackle proteins not amenable to x-ray crystallography or nuclear magnetic resonance. This research complements and expands the information available from more widely used, lower-resolution approaches. The new methods can be conducted on unmodified, commercially available instruments, increasing the accessibility of high-resolution measurements.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在化学系化学测量和成像项目的支持下，加州大学河滨分校的Ryan Julian教授和他的团队正在开发方法，以提高我们确定蛋白质结构的能力。蛋白质是生物学中多种重要功能的关键角色，包括作为能量工厂和细胞内部和细胞之间的通信。朱利安实验室正在开发新的方法，可以揭示蛋白质分子不同部分之间的距离，提供高分辨率的结构，有助于理解蛋白质的功能，以及如何在分子水平上操纵它们的功能。使用的主要工具是质谱法，这是一种快速的技术，可以用于少量的样品。质谱法结构测定能力的增强正在加速我们对关键生物行为体的理解。一群不同的研究生和本科生正在进行这项研究，并接受有价值的培训，这将使他们为未来推动科学和技术的界限做好准备。朱利安博士和他的团队还致力于针对弱势群体的高中生的推广工作。Julian小组正在开发新的方法，利用特定残基之间的能量转移和共价交联来确定高分辨率的蛋白质结构，以便建立多个定义良好的距离约束，这些距离约束可以与计算结合使用，以产生原子定义的气相结构。能量转移方法在确定高分辨率结构方面具有几个关键优势，包括：1)直接探测蛋白质亚结构，允许确定单个蛋白质中的多个距离约束；2)使用天然残基作为供体和受体，允许通过标准的定点诱变安装任何所需的氨基酸；3)极具选择性的化学键光化学裂解提供了高灵敏度和明确的结果解释。利用质谱的速度和灵敏度，气相结构生物学可以处理不适合x射线晶体学或核磁共振的蛋白质。这项研究补充并扩展了从更广泛使用的低分辨率方法中获得的信息。新方法可以在未经修改的商用仪器上进行，增加了高分辨率测量的可及性。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Differentiation of peptide isomers by excited-state photodissociation and ion–molecule interactions

通过激发态光解和离子-分子相互作用区分肽异构体

• DOI: 10.1039/d0cp04111d
• 发表时间: 2020
• 期刊: Physical Chemistry Chemical Physics
• 影响因子: 3.3
• 作者: Van Orman, Brielle L.;Wu, Hoi-Ting;Julian, Ryan R.
• 通讯作者: Julian, Ryan R.

Probing the Stability of Proline Cis/Trans Isomers in the Gas Phase with Ultraviolet Photodissociation

用紫外光解法探讨脯氨酸顺/反异构体在气相中的稳定性

• DOI: 10.1021/jasms.0c00242
• 发表时间: 2020
• 期刊: Journal of the American Society for Mass Spectrometry
• 影响因子: 3.2
• 作者: Silzel, Jacob W.;Murphree, Taylor A.;Paranji, Rajan K.;Guttman, Miklos M.;Julian, Ryan R.
• 通讯作者: Julian, Ryan R.

Efficient Isothiocyanate Modification of Peptides Facilitates Structural Analysis by Radical-Directed Dissociation

• DOI: 10.1021/jasms.1c00237
• 发表时间: 2022-08-03
• 期刊: JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
• 影响因子: 3.2
• 作者: Lambeth, Tyler R.;Julian, Ryan R.
• 通讯作者: Julian, Ryan R.

Modifying the internal substituents of self-assembled cages controls their molecular recognition and optical properties

修饰自组装笼的内部取代基可控制其分子识别和光学性质

• DOI: 10.1039/d2dt01451c
• 发表时间: 2022
• 期刊: Dalton Transactions
• 影响因子: 4
• 作者: Woods, Connor Z.;Wu, Hoi-Ting;Ngai, Courtney;da Camara, Bryce;Julian, Ryan R.;Hooley, Richard J.
• 通讯作者: Hooley, Richard J.

First in Human Evaluation and Dosimetry Calculations for Peptide 124I-p5+14—a Novel Radiotracer for the Detection of Systemic Amyloidosis Using PET/CT Imaging

首次对肽 124I-p5 14-a 新型放射性示踪剂进行人体评估和剂量计算，用于使用 PET/CT 成像检测系统性淀粉样变性

• DOI: 10.1007/s11307-021-01681-2
• 发表时间: 2022
• 期刊: Molecular Imaging and Biology
• 影响因子: 3.1
• 作者: Wall, Jonathan S.;Martin, Emily B.;Endsley, Aaron;Stuckey, Alan C.;Williams, Angela D.;Powell, Dustin;Whittle, Bryan;Hall, Sarah;Lambeth, Tyler R.;Julian, Ryan R.
• 通讯作者: Julian, Ryan R.