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Structural basis of lipid-droplet localization of 17-beta-hydroxysteroid dehydrogenase 13

Author

Listed:
  • Shenping Liu

    (Pfizer Inc)

  • Ruth F. Sommese

    (Pfizer Inc)

  • Nicole L. Nedoma

    (Pfizer Inc)

  • Lucy Mae Stevens

    (Pfizer Inc)

  • Jason K. Dutra

    (Pfizer Inc)

  • Liying Zhang

    (Pfizer Inc
    Merck Research Laboratories)

  • David J. Edmonds

    (Pfizer Inc
    Roche)

  • Yang Wang

    (Pfizer Inc)

  • Michelle Garnsey

    (Pfizer Inc)

  • Michelle F. Clasquin

    (Pfizer Inc)

Abstract

Hydroxysteroid 17-beta-dehydrogenase 13 (HSD17B13) is a hepatic lipid droplet-associated enzyme that is upregulated in patients with non-alcoholic fatty liver disease. Recently, there have been several reports that predicted loss of function variants in HSD17B13 protect against the progression of steatosis to non-alcoholic steatohepatitis with fibrosis and hepatocellular carcinoma. Here we report crystal structures of full length HSD17B13 in complex with its NAD+ cofactor, and with lipid/detergent molecules and small molecule inhibitors from two distinct series in the ligand binding pocket. These structures provide insights into a mechanism for lipid droplet-associated proteins anchoring to membranes as well as a basis for HSD17B13 variants disrupting function. Two series of inhibitors interact with the active site residues and the bound cofactor similarly, yet they occupy different paths leading to the active site. These structures provide ideas for structure-based design of inhibitors that may be used in the treatment of liver disease.

Suggested Citation

  • Shenping Liu & Ruth F. Sommese & Nicole L. Nedoma & Lucy Mae Stevens & Jason K. Dutra & Liying Zhang & David J. Edmonds & Yang Wang & Michelle Garnsey & Michelle F. Clasquin, 2023. "Structural basis of lipid-droplet localization of 17-beta-hydroxysteroid dehydrogenase 13," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40766-0
    DOI: 10.1038/s41467-023-40766-0
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    References listed on IDEAS

    as
    1. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    2. Wen Su & Sijin Wu & Yongliang Yang & Yanlin Guo & Haibo Zhang & Jie Su & Lei Chen & Zhuo Mao & Rongfeng Lan & Rong Cao & Chunjiong Wang & Hu Xu & Cong Zhang & Sha Li & Min Gao & Xiaocong Chen & Zhiyou, 2022. "Phosphorylation of 17β-hydroxysteroid dehydrogenase 13 at serine 33 attenuates nonalcoholic fatty liver disease in mice," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    3. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
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