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<p>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 <i>Saccharomyces cerevisiae</i> (<i>Sc</i>SDH) in apo (3.36 Å) and ubiquinone-1-bound (3.25 Å) states, revealing subunits architecture and quinone-binding sites (Q<sub>p</sub>). <i>Sc</i>SDH 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 (<i>K</i><sub>i</sub> = 0.019 μM) and reduced zebrafish toxicity (LC<sub>50</sub> (96 h) = 1.01 mg a.i./L). This study elucidates the structure of fungal SDH and demonstrates the potential of <i>Sc</i>SDH for rational design of next-generation fungicides, addressing fungal resistance and environmental toxicity in agriculture.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月8日

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  • 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

摘要

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.