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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
    1. Tao Long & Yingyuan Sun & Abdirahman Hassan & Xiaofeng Qi & Xiaochun Li, 2020. "Structure of nevanimibe-bound tetrameric human ACAT1," Nature, Nature, vol. 581(7808), pages 339-343, May.
    2. Yang Liu & Xiaofeng Qi & Linda Donnelly & Nadia Elghobashi-Meinhardt & Tao Long & Rich W. Zhou & Yingyuan Sun & Boyuan Wang & Xiaochun Li, 2022. "Mechanisms and inhibition of Porcupine-mediated Wnt acylation," Nature, Nature, vol. 607(7920), pages 816-822, July.
    3. 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.
    4. 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.
    5. Weinan Du & Luchang Zhang & Adina Brett-Morris & Brittany Aguila & Janos Kerner & Charles L. Hoppel & Michelle Puchowicz & Dolors Serra & Laura Herrero & Brian I. Rini & Steven Campbell & Scott M. Wel, 2017. "HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism," Nature Communications, Nature, vol. 8(1), pages 1-12, December.
    6. Chengcheng Guan & Yange Niu & Si-Cong Chen & Yunlu Kang & Jing-Xiang Wu & Koji Nishi & Catherine C. Y. Chang & Ta-Yuan Chang & Tuoping Luo & Lei Chen, 2020. "Structural insights into the inhibition mechanism of human sterol O-acyltransferase 1 by a competitive inhibitor," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    7. Qing Zhang & Deqiang Yao & Bing Rao & Liyan Jian & Yang Chen & Kexin Hu & Ying Xia & Shaobai Li & Yafeng Shen & An Qin & Jie Zhao & Lu Zhou & Ming Lei & Xian-Cheng Jiang & Yu Cao, 2021. "The structural basis for the phospholipid remodeling by lysophosphatidylcholine acyltransferase 3," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
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