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

Nat Commun. 2021 Jun 9;12(1):3483. doi: 10.1038/s41467-021-23854-x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AAA Domain
  • ATPases Associated with Diverse Cellular Activities / antagonists & inhibitors
  • ATPases Associated with Diverse Cellular Activities / chemistry*
  • ATPases Associated with Diverse Cellular Activities / genetics
  • ATPases Associated with Diverse Cellular Activities / metabolism
  • Adenosine Triphosphatases / antagonists & inhibitors
  • Adenosine Triphosphatases / chemistry*
  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism
  • Binding Sites
  • Boron Compounds / chemistry*
  • Boron Compounds / pharmacology
  • Drug Resistance / genetics
  • Enzyme Activation / drug effects
  • Enzyme Activation / genetics
  • Mutation
  • Nucleotides / chemistry
  • Saccharomyces cerevisiae Proteins / antagonists & inhibitors
  • Saccharomyces cerevisiae Proteins / chemistry*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism


  • Boron Compounds
  • Nucleotides
  • Saccharomyces cerevisiae Proteins
  • 1,2-dihydro-1-hydroxy-6-methyl-2-(propanesulfonyl)-thieno(3,2D)(1,2,3)-diazaborine
  • Adenosine Triphosphatases
  • AFG2 protein, S cerevisiae
  • ATPases Associated with Diverse Cellular Activities