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Publication Abstract from PubMed

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.

Structural basis for inhibition of the AAA-ATPase Drg1 by diazaborine.,Prattes M, Grishkovskaya I, Hodirnau VV, Rossler I, Klein I, Hetzmannseder C, Zisser G, Gruber CC, Gruber K, Haselbach D, Bergler H Nat Commun. 2021 Jun 9;12(1):3483. doi: 10.1038/s41467-021-23854-x. PMID:34108481^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.