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TitleStructural insights into the inhibition mechanism of fungal GWT1 by manogepix.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 9194, Year 2024
Publish dateOct 24, 2024
AuthorsXinli Dai / Xuanzhong Liu / Jialu Li / Hui Chen / Chuangye Yan / Yaozong Li / Hanmin Liu / Dong Deng / Xiang Wang /
PubMed AbstractGlycosylphosphatidylinositol (GPI) acyltransferase is crucial for the synthesis of GPI-anchored proteins. Targeting the fungal glycosylphosphatidylinositol acyltransferase GWT1 by manogepix is a ...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.
External linksNat Commun / PubMed:39448635 / PubMed Central
MethodsEM (single particle)
Resolution3.37 - 3.55 Å
Structure data

38374

8xij

EMDB-38374, PDB-8xij:
Structure of acyltransferase GWT1 bound to palmitoyl-CoA
Method: EM (single particle) / Resolution: 3.37 Å

38375

8xik

EMDB-38375, PDB-8xik:
Structure of acyltransferase GWT1 in complex with manogepix(APX001A)
Method: EM (single particle) / Resolution: 3.55 Å

Chemicals

ChemComp-PKZ:
Palmitoyl-CoA

PDB-1lvi:
Unknown entry

Source
  • saccharomyces cerevisiae (brewer's yeast)
KeywordsMEMBRANE PROTEIN / complex / MEMBRANE PROTEIN/INHIBITOR / acyltransferase / MEMBRANE PROTEIN-INHIBITOR COMPLEX

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