7NKU

diazaborine bound Drg1(AFG2)

Summary for 7NKU

• Entry DOI: 10.2210/pdb7nku/pdb
• EMDB information: 12448
• Descriptor: ATPase family gene 2 protein, PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER, 6-METHYL-2(PROPANE-1-SULFONYL)-2H-THIENO[3,2-D][1,2,3]DIAZABORININ-1-OL (3 entities in total)
• Functional Keywords: drg1, afg2, ribosome maturation, aaa protein, diazaborine, inhibitor, ribosome
• Biological source: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast)
• Total number of polymer chains: 6
• Total formula weight: 517016.19

Authors

Prattes, M.,Bergler, H.,Haselbach, D. (deposition date: 2021-02-19, release date: 2021-06-23, Last modification date: 2025-04-09)

Primary citation

Prattes, M.,Grishkovskaya, I.,Hodirnau, V.V.,Rossler, I.,Klein, I.,Hetzmannseder, C.,Zisser, G.,Gruber, C.C.,Gruber, K.,Haselbach, D.,Bergler, H.
Structural basis for inhibition of the AAA-ATPase Drg1 by diazaborine.
Nat Commun, 12:3483-3483, 2021

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. 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.

PubMed: 34108481
DOI: 10.1038/s41467-021-23854-x

Experimental method

ELECTRON MICROSCOPY (3.4 Å)