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Structural insights into the inhibition mechanism of fungal GWT1 by manogepix

Author

Listed:
  • 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
    Sichuan University)

  • Dong Deng

    (Sichuan University
    Sichuan University
    Sichuan University)

  • Xiang Wang

    (Sichuan University
    Sichuan University
    Sichuan University)

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.

Suggested Citation

  • Xinli Dai & Xuanzhong Liu & Jialu Li & Hui Chen & Chuangye Yan & Yaozong Li & Hanmin Liu & Dong Deng & Xiang Wang, 2024. "Structural insights into the inhibition mechanism of fungal GWT1 by manogepix," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53512-x
    DOI: 10.1038/s41467-024-53512-x
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    1. Boyang Zhao & Zhongzheng Cao & Yi Zheng & Phuong Nguyen & Alisa Bowen & Robert H. Edwards & Robert M. Stroud & Yi Zhou & Menno Lookeren Campagne & Fei Li, 2024. "Structural and mechanistic insights into a lysosomal membrane enzyme HGSNAT involved in Sanfilippo syndrome," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    2. Lie Wang & Hongwu Qian & Yin Nian & Yimo Han & Zhenning Ren & Hanzhi Zhang & Liya Hu & B. V. Venkataram Prasad & Arthur Laganowsky & Nieng Yan & Ming Zhou, 2020. "Structure and mechanism of human diacylglycerol O-acyltransferase 1," Nature, Nature, vol. 581(7808), pages 329-332, May.
    3. Xuewu Sui & Kun Wang & Nina L. Gluchowski & Shane D. Elliott & Maofu Liao & Tobias C. Walther & Robert V. Farese, 2020. "Structure and catalytic mechanism of a human triacylglycerol-synthesis enzyme," Nature, Nature, vol. 581(7808), pages 323-328, May.
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