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Mechanism of action for small-molecule inhibitors of triacylglycerol synthesis

Author

Listed:
  • Xuewu Sui

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

  • Kun Wang

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

  • Kangkang Song

    (University of Massachusetts Chan Medical School
    University of Massachusetts Chan Medical School)

  • Chen Xu

    (University of Massachusetts Chan Medical School
    University of Massachusetts Chan Medical School)

  • Jiunn Song

    (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)

  • Maofu Liao

    (Harvard Medical School
    Southern University of Science and Technology)

  • 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)

  • Tobias C. Walther

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

Abstract

Inhibitors of triacylglycerol (TG) synthesis have been developed to treat metabolism-related diseases, but we know little about their mechanisms of action. Here, we report cryo-EM structures of the TG-synthesis enzyme acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), a membrane bound O-acyltransferase (MBOAT), in complex with two different inhibitors, T863 and DGAT1IN1. Each inhibitor binds DGAT1’s fatty acyl-CoA substrate binding tunnel that opens to the cytoplasmic side of the ER. T863 blocks access to the tunnel entrance, whereas DGAT1IN1 extends further into the enzyme, with an amide group interacting with more deeply buried catalytic residues. A survey of DGAT1 inhibitors revealed that this amide group may serve as a common pharmacophore for inhibition of MBOATs. The inhibitors were minimally active against the related MBOAT acyl-CoA:cholesterol acyltransferase 1 (ACAT1), yet a single-residue mutation sensitized ACAT1 for inhibition. Collectively, our studies provide a structural foundation for developing DGAT1 and other MBOAT inhibitors.

Suggested Citation

  • Xuewu Sui & Kun Wang & Kangkang Song & Chen Xu & Jiunn Song & Chia-Wei Lee & Maofu Liao & Robert V. Farese & Tobias C. Walther, 2023. "Mechanism of action for small-molecule inhibitors of triacylglycerol synthesis," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38934-3
    DOI: 10.1038/s41467-023-38934-3
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    References listed on IDEAS

    as
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