The Translation Inhibitor Rocaglamide Targets a Bimolecular Cavity between eIF4A and Polypurine RNA.
Mol Cell
; 73(4): 738-748.e9, 2019 02 21.
Article
em En
| MEDLINE
| ID: mdl-30595437
A class of translation inhibitors, exemplified by the natural product rocaglamide A (RocA), isolated from Aglaia genus plants, exhibits antitumor activity by clamping eukaryotic translation initiation factor 4A (eIF4A) onto polypurine sequences in mRNAs. This unusual inhibitory mechanism raises the question of how the drug imposes sequence selectivity onto a general translation factor. Here, we determined the crystal structure of the human eIF4A1â
ATP analogâ
RocAâ
polypurine RNA complex. RocA targets the "bi-molecular cavity" formed characteristically by eIF4A1 and a sharply bent pair of consecutive purines in the RNA. Natural amino acid substitutions found in Aglaia eIF4As changed the cavity shape, leading to RocA resistance. This study provides an example of an RNA-sequence-selective interfacial inhibitor fitting into the space shaped cooperatively by protein and RNA with specific sequences.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ribossomos
/
Biossíntese de Proteínas
/
Benzofuranos
/
RNA
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Inibidores da Síntese de Proteínas
/
Fator de Iniciação 4A em Eucariotos
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Mol Cell
Ano de publicação:
2019
Tipo de documento:
Article