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Structural basis for inhibition of the AAA-ATPase Drg1 by diazaborine

Author

Listed:
  • Michael Prattes

    (Institute of Molecular Biosciences, University of Graz
    BioTechMed-Graz)

  • Irina Grishkovskaya

    (Research Institute of Molecular Pathology (IMP), Vienna BioCenter)

  • Victor-Valentin Hodirnau

    (Institute of Science and Technology Austria)

  • Ingrid Rössler

    (Institute of Molecular Biosciences, University of Graz
    BioTechMed-Graz)

  • Isabella Klein

    (Institute of Molecular Biosciences, University of Graz)

  • Christina Hetzmannseder

    (Institute of Molecular Biosciences, University of Graz)

  • Gertrude Zisser

    (Institute of Molecular Biosciences, University of Graz)

  • Christian C. Gruber

    (Institute of Molecular Biosciences, University of Graz)

  • Karl Gruber

    (Institute of Molecular Biosciences, University of Graz
    BioTechMed-Graz
    Field of Excellence BioHealth - University of Graz)

  • David Haselbach

    (Research Institute of Molecular Pathology (IMP), Vienna BioCenter)

  • Helmut Bergler

    (Institute of Molecular Biosciences, University of Graz
    BioTechMed-Graz
    Field of Excellence BioHealth - University of Graz)

Abstract

The hexameric AAA-ATPase Drg1 is a key factor in eukaryotic ribosome biogenesis and initiates cytoplasmic maturation of the large ribosomal subunit by releasing the shuttling maturation factor Rlp24. Drg1 monomers contain two AAA-domains (D1 and D2) that act in a concerted manner. Rlp24 release is inhibited by the drug diazaborine which blocks ATP hydrolysis in D2. The mode of inhibition was unknown. Here we show the first cryo-EM structure of Drg1 revealing the inhibitory mechanism. Diazaborine forms a covalent bond to the 2′-OH of the nucleotide in D2, explaining its specificity for this site. As a consequence, the D2 domain is locked in a rigid, inactive state, stalling the whole Drg1 hexamer. Resistance mechanisms identified include abolished drug binding and altered positioning of the nucleotide. Our results suggest nucleotide-modifying compounds as potential novel inhibitors for AAA-ATPases.

Suggested Citation

  • Michael Prattes & Irina Grishkovskaya & Victor-Valentin Hodirnau & Ingrid Rössler & Isabella Klein & Christina Hetzmannseder & Gertrude Zisser & Christian C. Gruber & Karl Gruber & David Haselbach & H, 2021. "Structural basis for inhibition of the AAA-ATPase Drg1 by diazaborine," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23854-x
    DOI: 10.1038/s41467-021-23854-x
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    Cited by:

    1. Chengying Ma & Damu Wu & Qian Chen & Ning Gao, 2022. "Structural dynamics of AAA + ATPase Drg1 and mechanism of benzo-diazaborine inhibition," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Lisa Kofler & Lorenz Grundmann & Magdalena Gerhalter & Michael Prattes & Juliane Merl-Pham & Gertrude Zisser & Irina Grishkovskaya & Victor-Valentin Hodirnau & Martin Vareka & Rolf Breinbauer & Stefan, 2024. "The novel ribosome biogenesis inhibitor usnic acid blocks nucleolar pre-60S maturation," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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