Understanding Evolution of Protein Function Through Design

通过设计了解蛋白质功能的进化

• 批准号: 10798959
• 负责人: Ivan V Korendovych
• 金额: $ 13.38万
• 依托单位: SYRACUSE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10798959
• 关键词: Adopted; Amyloid; Catalysis; Chemicals; Communities; Complex; Development; Directed Molecular Evolution; Drug resistance; Engineering; Enzymes; Evolution; Goals; Health; Knowledge; Light; Metals; Methods; Molecular; Nature; Neurodegenerative Disorders; Peptides; Pharmaceutical Preparations; Property; Protein Engineering; Proteins; Reaction; Research; Role; Scaffolding Protein; Scientist; Structure; Structure-Activity Relationship; Toxic effect; Work; catalyst; chemical reaction; cofactor; combat; design; improved; insight; interest; novel strategies; pathogen; programs; protein folding; protein function; self assembly; tool

The work proposed in Project 1 is based on the observation that one can design short Catalytic AMyloid- forming Peptides (CAMPs) to catalyze chemical reactions with high efficiency in addition to their own self- assembly. The goals of the proposed work are: 1. to understand the structural and mechanistic basis for the very high activity of CAMPs; 2. to achieve improved catalytic efficiency and substrate selectivity in CAMPs; 3. to create amyloid-organic frameworks, a new class of catalytic materials; 4. to develop complex multifunctional, light-driven and regulated CAMPs with tunable properties for synthesis of complex products. Development and characterization of catalytic amyloids will advance several fields of biomedical importance. It will set important structural and functional reference points for the broad community of scientists interested in the role of amyloids in protein folding, catalysis and health The structure-activity relationships and structural insights generated in the proposed work will help us better understand the mechanisms of amyloid toxicity and will improve our knowledge of the structures adopted by more complex amyloid-forming proteins. In addition to its practical value, this research program will have a profound impact on our understanding of the fundamental aspects of catalysis. Project 2 aims to develop a new NMR-based experimental approach to guide directed evolution to fully realize its potential in repurposing enzymes for new functions. Specifically we will: 1. gain a thorough understanding of the limits and the applicability of the method; 2. Independently validate the approach in different protein scaffolds; 3. use NMR guided directed evolution to create high efficient and selective catalysts for practically important chemical transformations. Project 3. The ability of pathogens to neutralize drugs via a newly developed catalytic activity is one of the mechanisms of drug resistance. Therefore, a deeper understanding of the factors that determine the ability of proteins to catalyze new chemical transformations is of paramount importance. We aim to determine the factors that guide evolution of protein function at a molecular level and use these principles to create catalysts for chemical transformations not found in nature. We will combine a minimalist computational approach with sophisticated protein engineering tools to create new protein catalysts for a number of different chemical transformations including those that require metal cofactors.

在项目1中提出的工作是基于这样的观察，即可以设计短的催化淀粉状- 形成肽（CAMPs），除了自身的作用外，还能高效催化化学反应， 组装件.本文的主要工作目标是：1.去理解这个世界的结构和机械基础 CAMPs活性高; 2.以实现CAMP中改进的催化效率和底物选择性; 3.到 创建淀粉样有机框架，一类新的催化材料; 4.开发复杂的多功能， 光驱动和调节的cAMP，具有可调的性质，用于合成复杂的产物。发展和 催化性淀粉样蛋白的表征将推进几个具有生物医学重要性的领域。它将设置重要的 为广大对淀粉样蛋白作用感兴趣的科学家提供结构和功能参考点 在蛋白质折叠，催化和健康的结构活性关系和结构的见解产生的 拟议的工作将帮助我们更好地了解淀粉样蛋白毒性的机制，并将提高我们的知识 更复杂的淀粉样蛋白所采用的结构。除了实用价值， 研究计划将对我们理解催化的基本方面产生深远的影响。 项目2旨在开发一种新的基于NMR的实验方法，以指导定向进化， 实现其在重新利用酶的新功能方面的潜力。具体来说，我们将：1。获得彻底的 了解方法的局限性和适用性; 2.在不同的环境中独立验证方法 蛋白质支架; 3.利用核磁共振引导的定向进化，创造高效和选择性的催化剂， 重要的化学变化。 项目3。病原体通过新开发的催化活性来中和药物的能力是其中之一。 耐药性的机制。因此，更深入地了解决定能力的因素 蛋白质催化新的化学转化是至关重要的。我们的目标是确定 在分子水平上指导蛋白质功能进化的因素，并利用这些原则来创造催化剂 自然界中没有的化学变化。我们将结合联合收割机的最低限度的计算方法， 复杂的蛋白质工程工具，为许多不同的化学物质创造新的蛋白质催化剂， 包括那些需要金属辅因子的转化。

项目成果

Synergistic Interactions Are Prevalent in Catalytic Amyloids.

• DOI: 10.1002/cbic.202000205
• 发表时间: 2020-09-14
• 期刊: Chembiochem : a European journal of chemical biology
• 作者: Marshall LR;Jayachandran M;Lengyel-Zhand Z;Rufo CM;Kriews A;Kim MC;Korendovych IV
• 通讯作者: Korendovych IV

Fishing for Catalysis: Experimental Approaches to Narrowing Search Space in Directed Evolution of Enzymes.

• DOI: 10.1021/jacsau.3c00315
• 发表时间: 2023-09-25
• 期刊: JACS AU
• 影响因子: 8
• 作者: Marshall, Liam R;Bhattacharya, Sagar;Korendovych, Ivan V
• 通讯作者: Korendovych, Ivan V

A redox-mediated Kemp eliminase.

• DOI: 10.1038/ncomms14876
• 发表时间: 2017-03-28
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Li A;Wang B;Ilie A;Dubey KD;Bange G;Korendovych IV;Shaik S;Reetz MT
• 通讯作者: Reetz MT

Editorial overview: The many facets of protein design: from self-assembled materials to vaccines.

编辑概述：蛋白质设计的多个方面：从自组装材料到疫苗。

• DOI: 10.1016/j.sbi.2018.10.004
• 发表时间: 2018
• 期刊: Current opinion in structural biology
• 影响因子: 6.8
• 作者: Korendovych,IvanV;Ghirlanda,Giovanna
• 通讯作者: Ghirlanda,Giovanna

Catalytic amyloids: Is misfolding folding?

• DOI: 10.1016/j.cbpa.2021.06.010
• 发表时间: 2021-10
• 期刊: Current opinion in chemical biology
• 影响因子: 7.8
• 作者: Marshall LR;Korendovych IV
• 通讯作者: Korendovych IV