The drug diazaborine blocks ribosome biogenesis by inhibiting the AAA-ATPase Drg1

J Biol Chem. 2014 Feb 14;289(7):3913-22. doi: 10.1074/jbc.M113.536110. Epub 2013 Dec 26.

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.

Keywords: AAA-ATPases; ATPases; Diazaborine; Drug Action; Enzyme Inhibitors; Protein-Drug Interactions; Ribosome Assembly; Small Molecule Inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / antagonists & inhibitors*
  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism
  • Adenosine Triphosphate / genetics
  • Adenosine Triphosphate / metabolism
  • Binding Sites
  • Boron Compounds / chemistry
  • Boron Compounds / pharmacology*
  • Cytoplasm / enzymology
  • Cytoplasm / genetics
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Ribosomal Proteins / biosynthesis
  • Ribosomal Proteins / genetics
  • Ribosome Subunits, Large, Eukaryotic / genetics
  • Ribosome Subunits, Large, Eukaryotic / metabolism
  • Saccharomyces cerevisiae / enzymology*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / antagonists & inhibitors*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism

Substances

  • Boron Compounds
  • Enzyme Inhibitors
  • Ribosomal Proteins
  • Saccharomyces cerevisiae Proteins
  • Adenosine Triphosphate
  • Adenosine Triphosphatases
  • AFG2 protein, S cerevisiae