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The structure of phosphatidylinositol remodeling MBOAT7 reveals its catalytic mechanism and enables inhibitor identification

Author

Listed:
  • Kun Wang

    (Harvard T.H. Chan School of Public Health
    Harvard Medical School)

  • Chia-Wei Lee

    (Harvard T.H. Chan School of Public Health
    Harvard Medical School)

  • Xuewu Sui

    (Harvard T.H. Chan School of Public Health
    Harvard Medical School
    Texas A&M University)

  • Siyoung Kim

    (University of Chicago)

  • Shuhui Wang

    (Harvard Medical School)

  • Aidan B. Higgs

    (Harvard T.H. Chan School of Public Health
    Harvard Medical School)

  • Aaron J. Baublis

    (Harvard T.H. Chan School of Public Health
    Harvard Medical School
    Harvard T.H. Chan School of Public Health)

  • Gregory A. Voth

    (The University of Chicago)

  • Maofu Liao

    (Harvard Medical School
    Southern University of Science and Technology)

  • Tobias C. Walther

    (Harvard T.H. Chan School of Public Health
    Harvard Medical School
    Harvard T.H. Chan School of Public Health
    Broad Institute of MIT and Harvard)

  • Robert V. Farese

    (Harvard T.H. Chan School of Public Health
    Harvard Medical School
    Broad Institute of MIT and Harvard
    Memorial Sloan Kettering Cancer Center)

Abstract

Cells remodel glycerophospholipid acyl chains via the Lands cycle to adjust membrane properties. Membrane-bound O-acyltransferase (MBOAT) 7 acylates lyso-phosphatidylinositol (lyso-PI) with arachidonyl-CoA. MBOAT7 mutations cause brain developmental disorders, and reduced expression is linked to fatty liver disease. In contrast, increased MBOAT7 expression is linked to hepatocellular and renal cancers. The mechanistic basis of MBOAT7 catalysis and substrate selectivity are unknown. Here, we report the structure and a model for the catalytic mechanism of human MBOAT7. Arachidonyl-CoA and lyso-PI access the catalytic center through a twisted tunnel from the cytosol and lumenal sides, respectively. N-terminal residues on the ER lumenal side determine phospholipid headgroup selectivity: swapping them between MBOATs 1, 5, and 7 converts enzyme specificity for different lyso-phospholipids. Finally, the MBOAT7 structure and virtual screening enabled identification of small-molecule inhibitors that may serve as lead compounds for pharmacologic development.

Suggested Citation

  • Kun Wang & Chia-Wei Lee & Xuewu Sui & Siyoung Kim & Shuhui Wang & Aidan B. Higgs & Aaron J. Baublis & Gregory A. Voth & Maofu Liao & Tobias C. Walther & Robert V. Farese, 2023. "The structure of phosphatidylinositol remodeling MBOAT7 reveals its catalytic mechanism and enables inhibitor identification," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38932-5
    DOI: 10.1038/s41467-023-38932-5
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