The Drug Diazaborine Blocks Ribosome Biogenesis by Inhibiting the AAA-ATPase Drg1 |
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| Authors: | Mathias Loibl Isabella Klein Michael Prattes Claudia Schmidt Lisa Kappel Gertrude Zisser Anna Gungl Elmar Krieger Brigitte Pertschy Helmut Bergler |
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| Institution: | From the ‡Institut für Molekulare Biowissenschaften, Karl-Franzens-Universität Graz, A-8010 Graz, Austria and ;§Centre for Molecular and Biomolecular Informatics 260, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands |
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| Abstract: | The drug diazaborine is the only known inhibitor of ribosome biogenesis and specifically blocks large subunit formation in eukaryotic cells. However, the target of this drug and the mechanism of inhibition were unknown. Here we identify the AAA-ATPase Drg1 as a target of diazaborine. Inhibitor binding into the second AAA domain of Drg1 requires ATP loading and results in inhibition of ATP hydrolysis in this site. As a consequence the physiological activity of Drg1, i.e. the release of Rlp24 from pre-60S particles, is blocked, and further progression of cytoplasmic preribosome maturation is prevented. Our results identify the first target of an inhibitor of ribosome biogenesis and provide the mechanism of inhibition of a key step in large ribosomal subunit formation. |
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| Keywords: | ATPases Drug Action Enzyme Inhibitors Protein-Drug Interactions Ribosome Assembly AAA-ATPases Diazaborine Small Molecule Inhibitor |
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