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

Michael Prattes, Irina Grishkovskaya, Victor-Valentin Hodirnau, Ingrid Rössler, Isabella Klein, Christina Hetzmannseder, Gertrude Zisser, Christian C. Gruber, Karl Gruber, David Haselbach () and Helmut Bergler ()
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Michael Prattes: Institute of Molecular Biosciences, University of 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
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
David Haselbach: Research Institute of Molecular Pathology (IMP), Vienna BioCenter
Helmut Bergler: Institute of Molecular Biosciences, University of Graz

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23854-x

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