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Status |
Public on Dec 30, 2018 |
Title |
Ternary protein•drug•RNA interface explains RocA sequence selectivity and Aglaia resistance |
Organism |
Homo sapiens |
Experiment type |
Other
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Summary |
A novel class of translation inhibitors isolated from Aglaia plants, exemplified by Rocaglamide A (RocA), shows promise as an anti-cancer therapy. RocA converts its molecular target, translation initiation factor 4A (eIF4A), a DEAD-box protein, into a purine-selective RNA-binding protein that represses protein synthesis from a subset of mRNAs. This unusual mechanism of action raises the question of how the drug induces selectivity for polypurine sequences. Furthermore, as eIF4A is found in all eukaryotes, it is unclear how Aglaia resists the effects of RocA. Here, we assembled the Aglaia transcriptome de novo and identified highly specific mutations in eIF4A that enable it to evade RocA-dependent translation inhibition. Furthermore, we determined the crystal structure of the human eIF4A1•ATP analog•RocA•polypurine RNA complex. RocA binds residues mutated in Aglaia and intercalates between consecutive purines at a sharp RNA bend, revealing the structural basis of polypurine-selective translational inhibition by RocA in human and resistance in Aglaia.
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Overall design |
Ribosome,profiling
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Contributor(s) |
Iwasaki S, Iwasaki W, Takahashi M, Floor SN, Mito M, Ito T, Ingolia NT |
Citation(s) |
30595437 |
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Submission date |
Aug 16, 2017 |
Last update date |
Jul 25, 2021 |
Contact name |
Shintaro Iwasaki |
E-mail(s) |
shintaro.iwasaki@riken.jp
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Organization name |
RIKEN
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Department |
Cluster for Pioneering Research
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Street address |
S205 Bioscience Bldg. 2-1 Hirosawa
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City |
Wako |
State/province |
Saitama |
ZIP/Postal code |
351-0198 |
Country |
Japan |
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Platforms (1) |
GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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Samples (6)
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Relations |
BioProject |
PRJNA398585 |
SRA |
SRP115648 |
Supplementary file |
Size |
Download |
File type/resource |
GSE102720_RAW.tar |
2.7 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
Raw data are available in SRA |
Processed data provided as supplementary file |
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