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

Author

Listed:
  • Zhi-Wen Li

    (Central China Normal University)

  • Yuan-Hui Huang

    (Central China Normal University)

  • Ge Wei

    (Central China Normal University)

  • Zong-Wei Lu

    (Central China Normal University)

  • Yu-Xia Wang

    (Central China Normal University)

  • Guang-Rui Cui

    (Central China Normal University)

  • Jun-Ya Wang

    (Central China Normal University)

  • Xin-He Yu

    (Central China Normal University)

  • Yi-Xuan Fu

    (Central China Normal University)

  • Er-Di Fan

    (Central China Normal University)

  • Qiong-You Wu

    (Central China Normal University)

  • Xiao-Lei Zhu

    (Central China Normal University)

  • Ying Ye

    (Central China Normal University)

  • Guang-Fu Yang

    (Central China Normal University)

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.

Suggested Citation

  • 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, 2025. "Cryo-EM structure of the yeast Saccharomyces cerevisiae SDH provides a template for eco-friendly fungicide discovery," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64001-0
    DOI: 10.1038/s41467-025-64001-0
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