组装线多酮生物合成中模块间通信的结构基础

IF 12.9 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Nature chemical biology Pub Date : 2024-08-23 DOI:10.1038/s41589-024-01709-y
Dillon P. Cogan, Alexander M. Soohoo, Muyuan Chen, Yan Liu, Krystal L. Brodsky, Chaitan Khosla
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引用次数: 0

摘要

组装线多酮合成酶(PKS)是一种模块化的多酶系统,具有相当大的基因重编程潜力。了解它们如何沿着确定的活性位点序列选择性地运输生物合成中间体,可以利用它们合理地改变 PKS 的产物结构。为了研究 PKS 催化结构域和底物酰基载体蛋白(ACP)结构域之间的功能性相互作用,我们采用了一种双功能试剂来交联一条原型装配线--6-脱氧赤藓酮内酯 B 合成酶的瞬时结构域-结构域界面,并通过单颗粒低温电子显微镜(cryo-EM)来解析它们的结构。通过对低温电子显微镜数据进行每微粒图像统计分析,我们发现了酮合成酶(KS)和 ACP 结构域之间的相互作用,这种相互作用可区分模块内和模块间的交流,同时加强了催化循环过程中构象不对称的相关性。我们的发现为基于结构设计由来自不同天然组装线的生物合成模块组成的混合 PKSs 奠定了基础。
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Structural basis for intermodular communication in assembly-line polyketide biosynthesis

Assembly-line polyketide synthases (PKSs) are modular multi-enzyme systems with considerable potential for genetic reprogramming. Understanding how they selectively transport biosynthetic intermediates along a defined sequence of active sites could be harnessed to rationally alter PKS product structures. To investigate functional interactions between PKS catalytic and substrate acyl carrier protein (ACP) domains, we employed a bifunctional reagent to crosslink transient domain–domain interfaces of a prototypical assembly line, the 6-deoxyerythronolide B synthase, and resolved their structures by single-particle cryogenic electron microscopy (cryo-EM). Together with statistical per-particle image analysis of cryo-EM data, we uncovered interactions between ketosynthase (KS) and ACP domains that discriminate between intra-modular and inter-modular communication while reinforcing the relevance of conformational asymmetry during the catalytic cycle. Our findings provide a foundation for the structure-based design of hybrid PKSs comprising biosynthetic modules from different naturally occurring assembly lines.

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来源期刊
Nature chemical biology
Nature chemical biology 生物-生化与分子生物学
CiteScore
23.90
自引率
1.40%
发文量
238
审稿时长
12 months
期刊介绍: Nature Chemical Biology stands as an esteemed international monthly journal, offering a prominent platform for the chemical biology community to showcase top-tier original research and commentary. Operating at the crossroads of chemistry, biology, and related disciplines, chemical biology utilizes scientific ideas and approaches to comprehend and manipulate biological systems with molecular precision. The journal embraces contributions from the growing community of chemical biologists, encompassing insights from chemists applying principles and tools to biological inquiries and biologists striving to comprehend and control molecular-level biological processes. We prioritize studies unveiling significant conceptual or practical advancements in areas where chemistry and biology intersect, emphasizing basic research, especially those reporting novel chemical or biological tools and offering profound molecular-level insights into underlying biological mechanisms. Nature Chemical Biology also welcomes manuscripts describing applied molecular studies at the chemistry-biology interface due to the broad utility of chemical biology approaches in manipulating or engineering biological systems. Irrespective of scientific focus, we actively seek submissions that creatively blend chemistry and biology, particularly those providing substantial conceptual or methodological breakthroughs with the potential to open innovative research avenues. The journal maintains a robust and impartial review process, emphasizing thorough chemical and biological characterization.
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