The Drug Diazaborine Blocks Ribosome Biogenesis by Inhibiting the AAA-ATPase Drg1 [Enzymology]

December 26th, 2013 by Loibl, M., Klein, I., Prattes, M., Schmidt, C., Kappel, L., Zisser, G., Gungl, A., Krieger, E., Pertschy, B., Bergler, H.

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 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 pre-ribosome 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.