The Translation Inhibitor Rocaglamide Targets a Bimolecular Cavity between eIF4A and Polypurine RNA.
Adenylyl Imidodiphosphate
/ chemistry
Aglaia
/ chemistry
Amino Acid Substitution
Benzofurans
/ chemistry
Binding Sites
Drug Resistance
/ genetics
Eukaryotic Initiation Factor-4A
/ chemistry
HEK293 Cells
Humans
Models, Molecular
Molecular Structure
Mutation
Plant Proteins
/ chemistry
Protein Binding
Protein Biosynthesis
/ drug effects
Protein Interaction Domains and Motifs
Protein Synthesis Inhibitors
/ chemistry
RNA
/ chemistry
Ribosomes
/ chemistry
Structure-Activity Relationship
FMO
Ribo-Seq
Rocaglamide
X-ray
crystal structure
eIF4A
evolution
ribosome profiling
sequence specificity
translation
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
21 02 2019
21 02 2019
Historique:
received:
10
01
2018
revised:
23
07
2018
accepted:
15
11
2018
pubmed:
1
1
2019
medline:
25
6
2019
entrez:
1
1
2019
Statut:
ppublish
Résumé
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 eIF4A1⋅ATP analog⋅RocA⋅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.
Identifiants
pubmed: 30595437
pii: S1097-2765(18)30996-1
doi: 10.1016/j.molcel.2018.11.026
pmc: PMC6386617
mid: NIHMS1514203
pii:
doi:
Substances chimiques
Benzofurans
0
Plant Proteins
0
Protein Synthesis Inhibitors
0
Adenylyl Imidodiphosphate
25612-73-1
RNA
63231-63-0
rocaglamide
84573-16-0
Eukaryotic Initiation Factor-4A
EC 2.7.7.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
738-748.e9Subventions
Organisme : NIGMS NIH HHS
ID : P41 GM068933
Pays : United States
Organisme : NIGMS NIH HHS
ID : P50 GM102706
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR029668
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR027303
Pays : United States
Organisme : NIH HHS
ID : S10 OD018174
Pays : United States
Informations de copyright
Copyright © 2018 Elsevier Inc. All rights reserved.
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