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New Chemical Tools for Optically Controlled Protein Modification

用于光控蛋白质修饰的新化学工具

基本信息

批准号：
10645036
负责人：
Michael T Taylor
金额：
$ 29.38万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
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

项目摘要

Project Summary/Abstract Biocompatible chemical transformations that are promoted by light have become powerful tools in chemical biology by virtue of enabling spatiotemporal control over activity. Whilst genetically encoded photoactivatable tools have become mainstays in the bio-orthogonal toolbox, light driven conjugation methods that effectively interface with native biomolecular structures (no genetic encoding) under biologically relevant conditions, are comparatively limited. In this project, we will evolve a method recently developed by our group for the photobioconjugation of Tryptophan (Trp) residues using redox-active N-carbamoylpyridinium salts that engage Trp in photo-induced electron transfer. We will show that, by carefully modulating the optical and electrochemical properties of these reagents, that we will be able to both (1) dramatically enhance the kinetic capabilities of this labelling reaction and (2) enable the discovery of new mechanistic paradigms that promote this labelling chemistry. Moreover, we will demonstrate that, through careful manipulation of optical and electrochemical properties of the N-carbamoyl pyridinum salt reagent, that we will be able to invoke mechanistic control over Trp labelling in a wavelength-dependent fashion (i.e. we can control reaction mechanism with a given wavelength of light). This, in turn, will allow us to design new application-based experiments that can both command precise reaction outcomes and markedly expand the capabilities of photobioconjugation chemistry. Specifically, we will harness this optical and mechanistic control for the design of new activity-based sensing applications as well as through the design of proximity labelling approaches that we apply to the study of poorly understood processes in mitochondrial dynamics.

项目概要/摘要光促进的生物相容性化学转化已成为化学领域的强大工具生物学能够对活动进行时空控制。虽然基因编码可光激活工具已成为生物正交工具箱的支柱，光驱动的缀合方法可以有效地在生物学相关条件下与天然生物分子结构（无遗传编码）的界面，是比较有限。在这个项目中，我们将发展我们小组最近开发的一种方法使用具有氧化还原活性的 N-氨基甲酰吡啶鎓盐对色氨酸 (Trp) 残基进行光生物缀合光诱导电子转移中的 Trp。我们将证明，通过仔细调制光学和电化学这些试剂的特性，我们将能够（1）显着增强这种试剂的动力学能力标记反应并且（2）能够发现促进这种标记的新机制范例化学。此外，我们将证明，通过仔细操纵光学和电化学 N-氨基甲酰吡啶盐试剂的特性，我们将能够对色氨酸进行机械控制以波长相关的方式进行标记（即我们可以用给定的波长控制反应机制的光）。反过来，这将使我们能够设计新的基于应用的实验，这些实验既可以精确地控制反应结果并显着扩展光生物共轭化学的能力。具体来说，我们将利用这种光学和机械控制来设计新的基于活动的传感应用以及通过设计邻近标签方法，我们将其应用于研究知之甚少的过程在线粒体动力学中。