Structural Basis for Inhibition of the AAA-ATPase Drg1 by Diazaborine

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Jun 10

PMID 34108481

Citations 10

Authors

Michael Prattes

Irina Grishkovskaya

Victor-Valentin Hodirnau

Ingrid Rossler

Isabella Klein

Christina Hetzmannseder

Gertrude Zisser

Christian C Gruber

Karl Gruber

David Haselbach

Helmut Bergler

Affiliations

Soon will be listed here.

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.

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