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

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 () and Guang-Fu Yang ()
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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

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-64001-0

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