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Cryo-EM structure of Saccharomyces cerevisiae bc1 complex in Metyltetraprole-bound state
Structural highlights
FunctionA0A0G3F5W7_YEASX Component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex) that is part of the mitochondrial respiratory chain. The b-c1 complex mediates electron transfer from ubiquinol to cytochrome c. Contributes to the generation of a proton gradient across the mitochondrial membrane that is then used for ATP synthesis.[RuleBase:RU362117] Publication Abstract from PubMedCytochrome bc(1) (complex III) represents a significant target for the discovery of both drugs and fungicides. Metyltetraprole (MET) is commonly classified as a quinone site inhibitor (Q(o)I) 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 A; PYR, 2.42 A) and inhibitor-bound porcine complex III (MET, 2.53 A; PYR, 2,37 A) 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 Q(o) site. However, in porcine, MET acted as a dual-target inhibitor of both Q(o) and Q(i). 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. 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 J Am Chem Soc. 2024 Dec 11;146(49):33903-33913. doi: 10.1021/jacs.4c12595. Epub , 2024 Nov 27. PMID:39601138[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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