The Translation Inhibitor Rocaglamide Targets a Bimolecular Cavity between eIF4A and Polypurine RNA

Shintaro Iwasaki, Wakana Iwasaki, Mari Takahashi, Ayako Sakamoto, Chiduru Watanabe, Yuichi Shichino, Stephen N. Floor, Koichi Fujiwara, Mari Mito, Kosuke Dodo, Mikiko Sodeoka, Hiroaki Imataka, Teruki Honma, Kaori Fukuzawa, Takuhiro Ito, Nicholas T. Ingolia

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

Abstract

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. Iwasaki et al. resolve the structure of the human eIF4A1⋅AMPPNP⋅RocA⋅polypurine RNA complex and identify the natural amino acid substitutions in Aglaia eIF4As. These explain the molecular basis of RNA sequence selectivity provided by RocA and the resistance mechanism of the Aglaia plant, a natural source of RocA.

Original languageEnglish
Pages (from-to)738-748.e9
JournalMolecular Cell
Volume73
Issue number4
DOIs
Publication statusPublished - 2019 Feb 21
Externally publishedYes

Keywords

  • FMO
  • Ribo-Seq
  • Rocaglamide
  • X-ray
  • crystal structure
  • eIF4A
  • evolution
  • ribosome profiling
  • sequence specificity
  • translation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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