Journal
MOLECULAR CELL
Volume 73, Issue 4, Pages 738-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2018.11.026
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Funding
- Damon Runyon Cancer Research Foundation [DRR-37-15]
- Searle Scholars Program [11-SSP-229]
- National Institute of General Medical Sciences of the NIH [P50GM102706]
- Japan Society for the Promotion of Science (JSPS) [JP15H01548, JP17H05677, JP16H04756]
- RIKEN
- Takeda Science Foundation
- JSPS [JP17H05679, JP17H04998]
- AMED [JP18am0101082, JP18am0101113]
- AMED-CREST [JP18gm0710004]
- Human Frontier Science Program long-term fellowship
- NIH [S10RR029668, S10RR027303, OD018174, GM68933]
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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 center dot ATP analog center dot RocA center dot 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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