Cryo-EM structure of the yeast Saccharomyces cerevisiae SDH provides a template for eco-friendly fungicide discovery.

IF 15.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-10-08 DOI:10.1038/s41467-025-64001-0

Zhi-Wen Li,Yuan-Hui Huang,Ge Wei,Zong-Wei Lu,Yu-Xia Wang,Guang-Rui Cui,Jun-Ya Wang,Xin-He Yu,Yi-Xuan Fu,Er-Di Fan,Qiong-You Wu,Xiao-Lei Zhu,Ying Ye,Guang-Fu Yang

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引用次数: 0

Abstract

Succinate dehydrogenase (SDH) is a key fungicidal target, but rational inhibitors design has been impeded by the lack of fungal SDH structure. Here, we show the cryo-EM structure of SDH from Saccharomyces cerevisiae (ScSDH) in apo (3.36 Å) and ubiquinone-1-bound (3.25 Å) states, revealing subunits architecture and quinone-binding sites (Qp). ScSDH is classified as a heme-deficient type-D SDH, utilizing conserved redox centers (FAD, [2Fe-2S], [4Fe-4S] and [3Fe-4S] clusters) for electron transfer. A 3.23 Å structure with pydiflumetofen (PYD) identified critical interactions, including hydrogen bonds with Trp_SDHB194 and Tyr_SDHD120, and a cation-π interaction with Arg_SDHC97. Leveraging this, we designed a SDH inhibitor E8 (enprocymid), exhibiting significant fungicidal activity (Ki = 0.019 μM) and reduced zebrafish toxicity (LC50 (96 h) = 1.01 mg a.i./L). This study elucidates the structure of fungal SDH and demonstrates the potential of ScSDH for rational design of next-generation fungicides, addressing fungal resistance and environmental toxicity in agriculture.

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酵母Saccharomyces cerevisiae SDH的低温电镜结构为环保型杀菌剂的发现提供模板。

琥珀酸脱氢酶（SDH）是一个重要的杀真菌靶点，但由于缺乏真菌SDH结构，合理的抑制剂设计一直受到阻碍。在这里，我们展示了Saccharomyces cerevisiae （ScSDH）在载子（3.36 Å）和泛素-1结合（3.25 Å）状态下的SDH的低温电镜结构，揭示了亚基结构和醌结合位点（Qp）。ScSDH被归类为血红素缺陷型d型SDH，利用保守的氧化还原中心（FAD, [2Fe-2S]， [4Fe-4S]和[3Fe-4S]簇）进行电子转移。与pydiflumetofen （PYD）的3.23 Å结构确定了关键相互作用，包括与Trp_SDHB194和Tyr_SDHD120的氢键，以及与Arg_SDHC97的阳离子-π相互作用。利用这一点，我们设计了SDH抑制剂E8 (enprocyid)，具有显著的杀真菌活性（Ki = 0.019 μM），降低了斑马鱼的毒性（LC50 (96 h) = 1.01 mg a.i./L）。本研究阐明了真菌SDH的结构，并证明了ScSDH在合理设计下一代杀菌剂、解决农业真菌抗性和环境毒性问题方面的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.