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-Structure paper
Title | Structural basis for inhibition of the AAA-ATPase Drg1 by diazaborine. |
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Journal, issue, pages | Nat Commun, Vol. 12, Issue 1, Page 3483, Year 2021 |
Publish date | Jun 9, 2021 |
![]() | Michael Prattes / Irina Grishkovskaya / Victor-Valentin Hodirnau / Ingrid Rössler / Isabella Klein / Christina Hetzmannseder / Gertrude Zisser / Christian C Gruber / Karl Gruber / David Haselbach / Helmut Bergler / ![]() |
PubMed Abstract | 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. ...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. |
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Methods | EM (single particle) |
Resolution | 3.4 Å |
Structure data | EMDB-12448, PDB-7nku: |
Chemicals | ![]() ChemComp-AGS: ![]() ChemComp-TDB: |
Source |
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![]() | RIBOSOME / DRG1 / AFG2 / ribosome maturation / AAA protein / diazaborine / inhibitor |