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Structural insights into the inhibition mechanism of fungal GWT1 by manogepix
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Structural insights into the inhibition mechanism of fungal GWT1 by manogepix
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Journal Article
Structural insights into the inhibition mechanism of fungal GWT1 by manogepix
2024
Overview
Glycosylphosphatidylinositol (GPI) acyltransferase is crucial for the synthesis of GPI-anchored proteins. Targeting the fungal glycosylphosphatidylinositol acyltransferase GWT1 by manogepix is a promising antifungal strategy. However, the inhibitory mechanism of manogepix remains unclear. Here, we present cryo-EM structures of yeast GWT1 bound to the substrate (palmitoyl-CoA) and inhibitor (manogepix) at 3.3 Å and 3.5 Å, respectively. GWT1 adopts a unique fold with 13 transmembrane (TM) helixes. The palmitoyl-CoA inserts into the chamber among TM4, 5, 6, 7, and 12. The crucial residues (D145 and K155) located on the loop between TM4 and TM5 potentially bind to the GPI precursor, contributing to substrate recognition and catalysis, respectively. The antifungal drug, manogepix, occupies the hydrophobic cavity of the palmitoyl-CoA binding site, suggesting a competitive inhibitory mechanism. Structural analysis of resistance mutations elucidates the drug specificity and selectivity. These findings pave the way for the development of potent and selective antifungal drugs targeting GWT1.
Cryo-EM structures reveal how the first-in-class antifungal drug manogepix inhibits fungal GWT1, a key enzyme for GPI-anchored protein synthesis. The study uncovers manogepix’s competitive binding mechanism and explains drug resistance, offering insights for more effective antifungal therapies.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ Acyltransferases - antagonists & inhibitors
/ Acyltransferases - chemistry
/ Acyltransferases - metabolism
/ Antifungal Agents - chemistry
/ Antifungal Agents - pharmacology
/ biokemi
/ Fungal Proteins - antagonists & inhibitors
/ Fungal Proteins - metabolism
/ Fungi
/ Glycosylphosphatidylinositol
/ Humanities and Social Sciences
/ Inserts
/ Proteins
/ Saccharomyces cerevisiae - genetics
/ Saccharomyces cerevisiae - metabolism
/ Science
/ Yeast
