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. 2025 Oct 8;16(1):8936.
doi: 10.1038/s41467-025-64001-0.

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

Zhi-Wen Li #  1 , Yuan-Hui Huang #  1 , Ge Wei #  1 , Zong-Wei Lu  1 , Yu-Xia Wang  1 , Guang-Rui Cui  1 , Jun-Ya Wang  1 , Xin-He Yu  1 , Yi-Xuan Fu  1 , Er-Di Fan  1 , Qiong-You Wu  1 , Xiao-Lei Zhu  2 , Ying Ye  3 , Guang-Fu Yang  4
Affiliations

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

Zhi-Wen Li et al. Nat Commun. .

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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Conflict of interest statement

Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Overall architecture of the SDH from S. cerevisiae.
a Cryo-EM map of SDH at 3.36 Å resolution and cartoon representation of ScSDH. The SDH protein has a total length of 108 Å and a transmembrane portion of 40 Å. SDHA, SDHB, SDHC, and SDHD subunits are colored in blue, orange, green, and yellow individually. b Cartoon representation of SDHA subunits. FAD is shown as stick. All domains are color-coded. c Cartoon representation of SDHB subunits. FeS clusters are shown as spheres. All domains are color-coded. d Cartoon representation of hydrophobic transmembrane subunits SDHC and SDHD in front view and top view. The six transmembrane helices are labeled. PE phosphatidylethanolamine (shown as gray stick).
Fig. 2
Fig. 2. Comparison of transmembrane subunit structures between S. cerevisiae and S. scrofa.
a The alignment of ScSDH with S. scrofa SDH (Type C, PDB ID 1ZOY) in front view and top view. b Demonstration of heme-related amino acids in ScSDH with SsSDH. In SsSDH, D-102His and C-127His interact with heme, while in ScSDH, the allelic amino acids change to D-108Tyr and C-156His. c Top view of ScSDH and SsSDH. SDHC and SDHD alignment with surface representation. Sc, S. cerevisiae; Ss, S. scrofa. All subunits are color-coded. SDHC subunits are colored in green (Sc) and ice blue (Ss); SDHD subunits are colored in orange (Sc) and pink (Ss). PE and Heme are shown as gray stick.
Fig. 3
Fig. 3. Structure of the UQ1 bound in S. cerevisiae SDH.
a Determination of heme in SDH by absorbance spectrometry. Reduced heme has a characteristic absorption peak at 560 nm. The presence of heme can be detected in the reduced SsSDH, while it cannot be detected in the reduced ScSDH. b The electron transfer pathway of ScSDH. Prosthetic groups in the path of electron transfer are labeled with edge-to-edge distances. Four prosthetic groups, FAD, [2Fe-2S], [4Fe-4S], and [3Fe-4S] are required for electron transfer flow from succinate to ubiquinone. c The interaction of UQ1 with ScSDH. The UQ1 is surrounded with B_190Pro, B_194Trp, B_239Ile, C_94Ser, C_97Arg and D_120Tyr.
Fig. 4
Fig. 4. The binding site of Qp inhibitor PYD analysis in S. cerevisiae SDH.
a The binding mode between inhibitor PYD and target ScSDH in two views. PYD forms hydrogen bonds with B_194Trp, C_94Ser and D_120Tyr, and interacts with C_97Arg to form cation-π interactions. PYD is shown as stick, colored in yellow. b Comparison of porcine Qp sites bound to different inhibitors (including 3AEB, 3AE9, and 3AEE) with nearby amino acids showed that C_61Trp had different side chain orientations and underwent flipping in the presence of different inhibitors. c Inhibitor-bound Qp pocket and the alignments of Qp pocket between ScSDH (9KQ3) and SsSDH (3AEB). Due to changes in surrounding amino acids, the Qp pocket space in SsSDH is larger than that in ScSDH. Sc, S. cerevisiae; Ss, S. scrofa. 3AEB, 3AE9, 3AEE, and 9KQ3 are colored in blue, green, yellow, and purple.
Fig. 5
Fig. 5. Design strategy of PYD analogs and binding modes with S. cerevisiae SDH.
a Design protocol of the PYD analogs. b The binding mode of E8 with ScSDH. E8 forms hydrogen bonds with B_194Trp and D_120Tyr, and interacts with C_97Arg to form cation-π interactions. c Overlapping diagram of E8 (blue stick) and PYD (yellow stick) combined with ScSDH. Their combination mode is similar.
Fig. 6
Fig. 6. Protective activities of E8.
a Control effect of E8 against FHB in field trial. Three test plots were used per treatment. CK is no treatment. b DON toxin content and toxin inhibition of E8 treatments. Wheat samples collected using the 5-point sampling method were milled into flour, and the DON toxin content in the flour was assayed using HPLC, with the inhibition rate of the toxin calculated. c Average thousand grain weight and yield increase rate of E8 treatment. Test the weight of 1000 randomly selected wheat ears with the 5-point sampling method. d Growth of wheat ears of E8 treatment. Wheat ears infected with FBH turn black, while uninfected ears remain bright yellow. FBH fusarium head blight, DON deoxynivalenol, EC emulsifiable concentrate, SC suspension concentrate, AS aqueous solutions, CK control group.
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