title: The drug diazaborine blocks ribosome biogenesis by inhibiting the AAA-ATPase Drg1.
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.
authors.affiliation: From the Institut für Molekulare Biowissenschaften, Karl-Franzens-Universität Graz, A-8010 Graz, Austria and.
authors.forename: Mathias
authors.initials: M
authors.lastname: Loibl
authors.forename: Isabella
authors.initials: I
authors.lastname: Klein
authors.forename: Michael
authors.initials: M
authors.lastname: Prattes
authors.forename: Claudia
authors.initials: C
authors.lastname: Schmidt
authors.forename: Lisa
authors.initials: L
authors.lastname: Kappel
authors.forename: Gertrude
authors.initials: G
authors.lastname: Zisser
authors.forename: Anna
authors.initials: A
authors.lastname: Gungl
authors.forename: Elmar
authors.initials: E
authors.lastname: Krieger
authors.forename: Brigitte
authors.initials: B
authors.lastname: Pertschy
authors.forename: Helmut
authors.initials: H
authors.lastname: Bergler
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D001896:Boron Compounds / Q000737:chemistry / Q000494:pharmacology*; D003593:Cytoplasm / Q000201:enzymology / Q000235:genetics; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D012269:Ribosomal Proteins / Q000096:biosynthesis / Q000235:genetics; D054683:Ribosome Subunits, Large, Eukaryotic / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D001896:Boron Compounds; D004791:Enzyme Inhibitors; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; C463962:AFG2 protein, S cerevisiae
keywords: AAA-ATPases; ATPases; Diazaborine; Drug Action; Enzyme Inhibitors; Protein-Drug Interactions; Ribosome Assembly; Small Molecule Inhibitor