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Effects of Mutations in the Phenamacril-Binding Site of Fusarium Myosin-1 on Its Motor Function and Phenamacril Sensitivity

[Image: see text] Phenamacril is a Fusarium-specific fungicide used for Fusarium head blight management. The target of phenamacril is FgMyo1, the sole class I myosin in Fusarium graminearum. The point mutation S217L in FgMyo1 is responsible for the high resistance of F. graminearum to phenamacril. R...

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Autores principales: Ni, Tong, Yuan, Min, Ji, Huan-Hong, Tang, Guangfei, Chen, Yun, Ma, Zhonghua, Li, Xiang-dong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2020
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469408/
https://www.ncbi.nlm.nih.gov/pubmed/32905433
http://dx.doi.org/10.1021/acsomega.0c02886
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author Ni, Tong
Yuan, Min
Ji, Huan-Hong
Tang, Guangfei
Chen, Yun
Ma, Zhonghua
Li, Xiang-dong
author_facet Ni, Tong
Yuan, Min
Ji, Huan-Hong
Tang, Guangfei
Chen, Yun
Ma, Zhonghua
Li, Xiang-dong
author_sort Ni, Tong
collection PubMed
description [Image: see text] Phenamacril is a Fusarium-specific fungicide used for Fusarium head blight management. The target of phenamacril is FgMyo1, the sole class I myosin in Fusarium graminearum. The point mutation S217L in FgMyo1 is responsible for the high resistance of F. graminearum to phenamacril. Recent structural studies have shown that phenamacril binds to the 50 kDa cleft of the FgMyo1 motor domain, forming extensive interactions, including a hydrogen bond between the cyano group of phenamacril and the hydroxyl group of S217. Here, we produced FgMyo1(IQ2), a truncated FgMyo1 composed of the motor domain and two IQ motifs complexed with the F. graminearum calmodulin in insect Sf9 cells. Phenamacril potently inhibited both the basal and the actin-activated ATPase activities of FgMyo1(IQ2), with an IC(50) in a micromolar range. S217 mutations of FgMyo1(IQ2) substantially increased the IC(50) of phenamacril. S217T or S217L each increased the IC(50) of phenamacril for ∼60-fold, while S217A only increased the IC(50) for ∼4-fold. These results indicate that the hydroxyl group of S217 plays an important, but nonessential role in phenamacril binding and that the bulky side chain at the position 217 sterically hinders phenamacril binding. On the other hand, S217P, which might alter the local conformation of the phenamacril-binding site, completely abolished the phenamacril inhibition. Because the cyano group of phenamacril does not form discernible interactions with FgMyo1 other than the nonessential hydrogen bond with the S217 hydroxyl group, we propose the cyano group of phenamacril as a key modification site for the development of novel fungicides.
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spelling pubmed-74694082020-09-04 Effects of Mutations in the Phenamacril-Binding Site of Fusarium Myosin-1 on Its Motor Function and Phenamacril Sensitivity Ni, Tong Yuan, Min Ji, Huan-Hong Tang, Guangfei Chen, Yun Ma, Zhonghua Li, Xiang-dong ACS Omega [Image: see text] Phenamacril is a Fusarium-specific fungicide used for Fusarium head blight management. The target of phenamacril is FgMyo1, the sole class I myosin in Fusarium graminearum. The point mutation S217L in FgMyo1 is responsible for the high resistance of F. graminearum to phenamacril. Recent structural studies have shown that phenamacril binds to the 50 kDa cleft of the FgMyo1 motor domain, forming extensive interactions, including a hydrogen bond between the cyano group of phenamacril and the hydroxyl group of S217. Here, we produced FgMyo1(IQ2), a truncated FgMyo1 composed of the motor domain and two IQ motifs complexed with the F. graminearum calmodulin in insect Sf9 cells. Phenamacril potently inhibited both the basal and the actin-activated ATPase activities of FgMyo1(IQ2), with an IC(50) in a micromolar range. S217 mutations of FgMyo1(IQ2) substantially increased the IC(50) of phenamacril. S217T or S217L each increased the IC(50) of phenamacril for ∼60-fold, while S217A only increased the IC(50) for ∼4-fold. These results indicate that the hydroxyl group of S217 plays an important, but nonessential role in phenamacril binding and that the bulky side chain at the position 217 sterically hinders phenamacril binding. On the other hand, S217P, which might alter the local conformation of the phenamacril-binding site, completely abolished the phenamacril inhibition. Because the cyano group of phenamacril does not form discernible interactions with FgMyo1 other than the nonessential hydrogen bond with the S217 hydroxyl group, we propose the cyano group of phenamacril as a key modification site for the development of novel fungicides. American Chemical Society 2020-08-20 /pmc/articles/PMC7469408/ /pubmed/32905433 http://dx.doi.org/10.1021/acsomega.0c02886 Text en Copyright © 2020 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Ni, Tong
Yuan, Min
Ji, Huan-Hong
Tang, Guangfei
Chen, Yun
Ma, Zhonghua
Li, Xiang-dong
Effects of Mutations in the Phenamacril-Binding Site of Fusarium Myosin-1 on Its Motor Function and Phenamacril Sensitivity
title Effects of Mutations in the Phenamacril-Binding Site of Fusarium Myosin-1 on Its Motor Function and Phenamacril Sensitivity
title_full Effects of Mutations in the Phenamacril-Binding Site of Fusarium Myosin-1 on Its Motor Function and Phenamacril Sensitivity
title_fullStr Effects of Mutations in the Phenamacril-Binding Site of Fusarium Myosin-1 on Its Motor Function and Phenamacril Sensitivity
title_full_unstemmed Effects of Mutations in the Phenamacril-Binding Site of Fusarium Myosin-1 on Its Motor Function and Phenamacril Sensitivity
title_short Effects of Mutations in the Phenamacril-Binding Site of Fusarium Myosin-1 on Its Motor Function and Phenamacril Sensitivity
title_sort effects of mutations in the phenamacril-binding site of fusarium myosin-1 on its motor function and phenamacril sensitivity
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469408/
https://www.ncbi.nlm.nih.gov/pubmed/32905433
http://dx.doi.org/10.1021/acsomega.0c02886
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