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Series GSE102720 Query DataSets for GSE102720
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
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.
 
Overall design Ribosome,profiling
 
Contributor(s) Iwasaki S, Iwasaki W, Takahashi M, Floor SN, Mito M, Ito T, Ingolia NT
Citation(s) 30595437
Submission date Aug 16, 2017
Last update date Jul 25, 2021
Contact name Shintaro Iwasaki
E-mail(s) shintaro.iwasaki@riken.jp
Organization name RIKEN
Department Cluster for Pioneering Research
Street address S205 Bioscience Bldg. 2-1 Hirosawa
City Wako
State/province Saitama
ZIP/Postal code 351-0198
Country Japan
 
Platforms (1)
GPL20301 Illumina HiSeq 4000 (Homo sapiens)
Samples (6)
GSM2743733 ribo_naive_DMSO_rep1
GSM2743734 ribo_naive_DMSO_rep2
GSM2743735 ribo_naive_roca
Relations
BioProject PRJNA398585
SRA SRP115648

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE102720_RAW.tar 2.7 Mb (http)(custom) TAR (of TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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