EMD-39323
Cryo-EM structure of Saccharomyces cerevisiae bc1 complex in YF23694-bound state
EMD-39323
Single-particle2.74 Å
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Map released: 25/12/2024
Last modified: 25/12/2024
Sample Organism:
Saccharomyces cerevisiae
Sample: Cryo-EM structure of Saccharomyces cerevisiae bc1 complex in YF23694-bound state
Fitted models: 8yin (Avg. Q-score: 0.53)
Deposition Authors: Ye Y, Li ZW, Yang GF
Sample: Cryo-EM structure of Saccharomyces cerevisiae bc1 complex in YF23694-bound state
Fitted models: 8yin (Avg. Q-score: 0.53)
Deposition Authors: Ye Y, Li ZW, Yang GF
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Cryo-EM Structures Reveal the Unique Binding Modes of Metyltetraprole in Yeast and Porcine Cytochrome bc 1 Complex Enabling Rational Design of Inhibitors.
Wang YX,
Ye Y,
Li ZW,
Cui GR,
Shi XX,
Dong Y,
Jiang JJ,
Sun JY,
Guan ZW,
Zhang N,
Wu QY
,
Wang F
,
Zhu XL
,
Yang GF
(2024) J Am Chem Soc , 146 , 33903 - 33913
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(2024) J Am Chem Soc , 146 , 33903 - 33913
Abstract:
Cytochrome bc1 (complex III) represents a significant target for the discovery of both drugs and fungicides. Metyltetraprole (MET) is commonly classified as a quinone site inhibitor (QoI) that combats the G143A mutated isolate, which confers high resistance to strobilurin fungicides such as pyraclostrobin (PYR). The binding mode and antiresistance mechanism of MET remain unclear. Here, we determined the high-resolution structures of inhibitor-bound S. cerevisiae complex III (MET, 2.52 Å; PYR, 2.42 Å) and inhibitor-bound porcine complex III (MET, 2.53 Å; PYR, 2,37 Å) by cryo-electron microscopy. The distinct binding modes of MET and PYR were observed for the first time. Notably, the MET exhibited different binding modes in the two species. In S. cerevisiae, the binding site of MET was the same as PYR, serving as a Pm-type inhibitor of the Qo site. However, in porcine, MET acted as a dual-target inhibitor of both Qo and Qi. Based on the structural insights, a novel inhibitor (YF23694) was discovered and demonstrated excellent fungicidal activity against downy mildew and powdery mildew fungi. This work provides a new starting point for the design of the next generation of inhibitors to overcome the resistance.
Cytochrome bc1 (complex III) represents a significant target for the discovery of both drugs and fungicides. Metyltetraprole (MET) is commonly classified as a quinone site inhibitor (QoI) that combats the G143A mutated isolate, which confers high resistance to strobilurin fungicides such as pyraclostrobin (PYR). The binding mode and antiresistance mechanism of MET remain unclear. Here, we determined the high-resolution structures of inhibitor-bound S. cerevisiae complex III (MET, 2.52 Å; PYR, 2.42 Å) and inhibitor-bound porcine complex III (MET, 2.53 Å; PYR, 2,37 Å) by cryo-electron microscopy. The distinct binding modes of MET and PYR were observed for the first time. Notably, the MET exhibited different binding modes in the two species. In S. cerevisiae, the binding site of MET was the same as PYR, serving as a Pm-type inhibitor of the Qo site. However, in porcine, MET acted as a dual-target inhibitor of both Qo and Qi. Based on the structural insights, a novel inhibitor (YF23694) was discovered and demonstrated excellent fungicidal activity against downy mildew and powdery mildew fungi. This work provides a new starting point for the design of the next generation of inhibitors to overcome the resistance.