Catalytic methods for site-specific modification of natural proteins

天然蛋白质位点特异性修饰的催化方法

• 批准号: 1609654
• 负责人: Zachary Ball
• 金额: $ 51万
• 依托单位: William Marsh Rice University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1609654&HistoricalAwards=false
• 关键词: Catalytic; methods; site; specific; modification

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Zachary Ball from Rice University to investigate chemical reactions for protein modification. Proteins are incredibly large and complex molecules and selective alteration of proteins remains a daunting challenge. Nonetheless, chemically-modified proteins represent tantalizing opportunities. Applications of modified proteins include biomaterials for coatings or green energy and biological probes to understand, perturb, and inhibit biological pathways. Efforts under this award focus on developing new metal-mediated methods for protein modification. These novel methods allow the preparation of new sites with novel structures, reactivity, and biological properties. The research project is providing undergraduate students, graduate students, and postdoctoral fellows with training in synthetic organic and inorganic chemistry. In addition, these research participants are receiving training in techniques and modern analytical methods of protein chemistry. An integrated outreach program is introducing modern protein chemistry and analytical methods to local high school teachers and their students.In order to develop sequence-selective protein modification catalysts, this project employs rhodium(II) conjugates that enable modification of proteins, whether purified or in lysate, on the basis of molecular recognition. Catalytic modification provides a covalent readout for the presence and location of ligand binding, and thus allows identification of ligand-binding sites of "hit" compounds. The reactivity can also be harnessed to quantify inhibitors of weak, transient interactions that are difficult to study with existing methods. In a new direction, Chan-Lam coupling of boronate reagents allows copper-catalyzed modification of peptides and proteins, with unique sequence specificity. Unnatural chemical modification of metalloenzyme active sites has emerged as a powerful tool in metalloenzyme design. Boronate coupling promises to provide exciting new tools to build hybrid metalloproteins with new function and reactivity.

有了这个奖项，化学部的生命过程化学项目资助莱斯大学的Zachary Ball博士研究蛋白质修饰的化学反应。蛋白质是非常大和复杂的分子，选择性改变蛋白质仍然是一个艰巨的挑战。尽管如此，化学修饰的蛋白质代表着诱人的机会。改性蛋白质的应用包括用于涂层或绿色能量的生物材料和用于理解、干扰和抑制生物途径的生物探针。该奖项的重点是开发新的金属介导的蛋白质修饰方法。这些新方法允许制备具有新结构、反应性和生物学性质的新位点。该研究项目为本科生、研究生和博士后提供合成有机和无机化学方面的培训。此外，这些研究参与者正在接受蛋白质化学技术和现代分析方法的培训。该项目是一个综合推广项目，旨在向当地高中教师和学生介绍现代蛋白质化学和分析方法。为了开发序列选择性蛋白质修饰催化剂，该项目采用铑（II）结合物，可以在分子识别的基础上对蛋白质进行修饰，无论是纯化的还是溶解的蛋白质。催化修饰提供了配体结合的存在和位置的共价读数，从而允许鉴定“命中”化合物的配体结合位点。也可以利用反应性来量化难以用现有方法研究的弱的瞬时相互作用的抑制剂。在一个新的方向，硼酸酯试剂的Chan-Lam偶联允许铜催化的肽和蛋白质的修饰，具有独特的序列特异性。非天然化学修饰金属酶活性位点已成为金属酶设计的有力工具。硼酸酯偶联有望为构建具有新功能和反应活性的杂合金属蛋白提供令人兴奋的新工具。