Structural insights into the inhibition mechanism of fungal GWT1 by manogepix

Xinli Dai, Xuanzhong Liu, Jialu Li, Hui Chen, Chuangye Yan, Yaozong Li, Hanmin Liu (), Dong Deng () and Xiang Wang ()
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Xinli Dai: Sichuan University
Xuanzhong Liu: Sichuan University
Jialu Li: Sichuan University
Hui Chen: Sichuan University
Chuangye Yan: Tsinghua University
Yaozong Li: SE-901 87
Hanmin Liu: Sichuan University
Dong Deng: Sichuan University
Xiang Wang: Sichuan University

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-53512-x

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