EMD-39323

Single-particle
2.74 Å
EMD-39323 Deposition: 29/02/2024
Map released: 25/12/2024
Last modified: 25/12/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-39323

Cryo-EM structure of Saccharomyces cerevisiae bc1 complex in YF23694-bound state

EMD-39323

Single-particle
2.74 Å
EMD-39323 Deposition: 29/02/2024
Map released: 25/12/2024
Last modified: 25/12/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
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
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
PUBMED: 39601138
DOI: doi:10.1021/jacs.4c12595
ISSN: 1520-5126
ASTM: JACSAT
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.