8XIJ

Structure of acyltransferase GWT1 bound to palmitoyl-CoA

Summary for 8XIJ

• Entry DOI: 10.2210/pdb8xij/pdb
• EMDB information: 38374
• Descriptor: GPI-anchored wall transfer protein 1, Palmitoyl-CoA (2 entities in total)
• Functional Keywords: complex, membrane protein
• Biological source: Saccharomyces cerevisiae (brewer's yeast)
• Total number of polymer chains: 1
• Total formula weight: 56517.86

Authors

Dai, X.L.,Li, J.L.,Liu, X.Z.,Deng, D.,Yan, C.Y.,Wang, X. (deposition date: 2023-12-19, release date: 2024-10-02, Last modification date: 2025-07-02)

Primary citation

Dai, X.,Liu, X.,Li, J.,Chen, H.,Yan, C.,Li, Y.,Liu, H.,Deng, D.,Wang, X.
Structural insights into the inhibition mechanism of fungal GWT1 by manogepix.
Nat Commun, 15:9194-9194, 2024

PubMed 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.

PubMed: 39448635
DOI: 10.1038/s41467-024-53512-x

Experimental method

ELECTRON MICROSCOPY (3.37 Å)