Structural basis for inhibition of the AAA-ATPase Drg1 by diazaborine.
Nat Commun
; 12(1): 3483, 2021 06 09.
Article
en En
| MEDLINE
| ID: mdl-34108481
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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Compuestos de Boro
/
Adenosina Trifosfatasas
/
Proteínas de Saccharomyces cerevisiae
/
ATPasas Asociadas con Actividades Celulares Diversas
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Nat Commun
Asunto de la revista:
BIOLOGIA
/
CIENCIA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Austria