Structural basis of Fusarium myosin I inhibition by phenamacril.

Yuxin Zhou,Yuanping Gong,X Edward Zhou,Karsten Melcher,Melvin Bolton,Mingguo Zhou,Joseph S Brunzelle,Yuanye Zhu,Feng Zhang,Xiaoman Cao,H Eric Xu

doi:10.1371/journal.ppat.1008323

Abstract

Fusarium is a genus of filamentous fungi that includes species that cause devastating diseases in major staple crops, such as wheat, maize, rice, and barley, resulting in severe yield losses and mycotoxin contamination of infected grains. Phenamacril is a novel fungicide that is considered environmentally benign due to its exceptional specificity; it inhibits the ATPase activity of the sole class I myosin of only a subset of Fusarium species including the major plant pathogens F. graminearum, F. asiaticum and F. fujikuroi. To understand the underlying mechanisms of inhibition, species specificity, and resistance mutations, we have determined the crystal structure of phenamacril-bound F. graminearum myosin I. Phenamacril binds in the actin-binding cleft in a new allosteric pocket that contains the central residue of the regulatory Switch 2 loop and that is collapsed in the structure of a myosin with closed actin-binding cleft, suggesting that pocket occupancy blocks cleft closure. We have further identified a single, transferable phenamacril-binding residue found exclusively in phenamacril-sensitive myosins to confer phenamacril selectivity.

Highlights

Fusarium graminearum and F. asiaticum are plant pathogens that cause head blight, root rot, and seedling blight, diseases in wheat, maize, and barley, while F. fujikuroi is the causal agent of rice bakanae disease [1, 2]
We report the high-resolution structure of the phenamacril-bound myosin I motor domain of the major crop pathogen Fusarium graminearum, providing insight into the molecular mechanism of phenamacril action and resistance
These results are of broad significance for understanding the mode of actions of myosin-based fungicides and for designing novel myosin I inhibitors for crop protection and for treatment of human myosin dysfunction diseases

Summary

Introduction

Fusarium graminearum and F. asiaticum are plant pathogens that cause head blight, root rot, and seedling blight, diseases in wheat, maize, and barley, while F. fujikuroi is the causal agent of rice bakanae disease [1, 2] These pathogens cause both major yield losses and contamination of infested grains with mycotoxins, including deoxynivalenol, that are toxic to humans and animals. Phenamacril (experimental code JS399-19) is an effective and highly species-specific fungicide, even though it targets the conserved motor domain of myosins, which are found in all eukaryotes [3, 4]. Myosins have a highly conserved ATP- and myosin-binding motor domain, a force transducing lever arm containing one to several Ile/Gln (IQ) motifs, and a variable cargo interacting tail domain. ATP hydrolysis and release of the hydrolysis products is coupled to actin binding and a large “powerstroke” lever arm movement on actin (Fig 1A) [9,10,11,12,13]

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Discussion

Conclusion