光驱动合成蛋白的侧链安装
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光驱动合成蛋白的侧链安装

文章来源:体育比赛下注网址;时间:2020-09-27 13:02

本期文章:《自然》:Online/在线发表

英国牛津大学Benjamin G. Davis及Veronique Gouverneur课题组合作,揭示了光驱动合成蛋白侧链的翻译后安装。这一研究成果于2020年9月23日在线发表在《自然》上。

研究人员研发了可见光诱导的侧链在蛋白质脱氢丙氨酸残基上的安装,该过程是由碳中心自由基的形成介导的,该碳中心自由基可在水中形成C–C键。通过控制氧化还原反应,可以进行具有良好转化率和减少蛋白质破坏的位点选择性修饰。硼酸邻苯二酚酯衍生物的原位生成会产生RH2C•自由基,形成连接天然残基和PTM的天然键β-CH2-γ-CH2,而Fe(II)对吡啶基磺酰基衍生物的原位增强作用会导致RF2C•自由基的产生,形成带有二氟亚甲基标记的等效β-CH2-γ-CF2键。

这些反应具有化学耐受性,并且将各种功能(超过50个独特的残基/侧链)基团连接到各种蛋白质支架和位点。该方法可以在自由基前体存在敏感基团的情况下进行化学选择性引发,从而可以接入先前不相容的侧链。其产生的蛋白质功能和反应性可用于安装自由基前体,以产生均质的蛋白质自由基。可以通过同时感应化学和立体选择性来研究天然、非天然和CF2标记的翻译后修饰蛋白酶的功能;并合成具有杂合共价键活性的通用“烷基化蛋白”(即在一种极端情况下与小分子发生多种反应,或在另一种情况下通过良好的模仿选择性地与蛋白质目标发生反应)。翻译后对蛋白质进行修饰将可能有助于揭示和产生新的蛋白质功能。

据了解,翻译后修饰(PTM)大大扩展了自然界中蛋白质的结构和功能。尽管合成蛋白功能化策略可以产生PTM类似物,并形成多种具有潜在功能的非天然蛋白变异体,包括药物携带、追踪、成像和伴侣交联,但其可以引入的官能团范围十分有限。

附:英文原文

Title: Light-driven post-translational installation of reactive protein side chains

Author: Brian Josephson, Charlie Fehl, Patrick G. Isenegger, Simon Nadal, Tom H. Wright, Adeline W. J. Poh, Ben J. Bower, Andrew M. Giltrap, Lifu Chen, Christopher Batchelor-McAuley, Grace Roper, Oluwatobi Arisa, Jeroen B. I. Sap, Akane Kawamura, Andrew J. Baldwin, Shabaz Mohammed, Richard G. Compton, Veronique Gouverneur, Benjamin G. Davis

Issue&Volume: 2020-09-23

Abstract: Post-translational modifications (PTMs) greatly expand the structures and functions of proteins in nature1,2. Although synthetic protein functionalization strategies allow mimicry of PTMs3,4, as well as formation of unnatural protein variants with diverse potential functions, including drug carrying5, tracking, imaging6 and partner crosslinking7, the range of functional groups that can be introduced remains limited. Here we describe the visible-light-driven installation of side chains at dehydroalanine residues in proteins through the formation of carbon-centred radicals that allow C–C bond formation in water. Control of the reaction redox allows site-selective modification with good conversions and reduced protein damage. In situ generation of boronic acid catechol ester derivatives generates RH2C radicals that form the native (β-CH2–γ-CH2) linkage of natural residues and PTMs, whereas in situ potentiation of pyridylsulfonyl derivatives by Fe(II) generates RF2C radicals that form equivalent β-CH2–γ-CF2 linkages bearing difluoromethylene labels. These reactions are chemically tolerant and incorporate a wide range of functionalities (more than 50 unique residues/side chains) into diverse protein scaffolds and sites. Initiation can be applied chemoselectively in the presence of sensitive groups in the radical precursors, enabling installation of previously incompatible side chains. The resulting protein function and reactivity are used to install radical precursors for homolytic on-protein radical generation; to study enzyme function with natural, unnatural and CF2-labelled post-translationally modified protein substrates via simultaneous sensing of both chemo- and stereoselectivity; and to create generalized ‘alkylator proteins’ with a spectrum of heterolytic covalent-bond-forming activity (that is, reacting diversely with small molecules at one extreme or selectively with protein targets through good mimicry at the other). Post-translational access to such reactions and chemical groups on proteins could be useful in both revealing and creating protein function.

DOI: 10.1038/s41586-020-2733-7

Source: https://www.nature.com/articles/s41586-020-2733-7

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
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