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

Mol Cell. 2019 Feb 21;73(4):738-748.e9. doi: 10.1016/j.molcel.2018.11.026. Epub 2018 Dec 27.

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.

Keywords: FMO; Ribo-Seq; Rocaglamide; X-ray; crystal structure; eIF4A; evolution; ribosome profiling; sequence specificity; translation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylyl Imidodiphosphate / chemistry
  • Adenylyl Imidodiphosphate / metabolism
  • Aglaia / chemistry
  • Aglaia / genetics
  • Aglaia / metabolism
  • Amino Acid Substitution
  • Benzofurans / chemistry
  • Benzofurans / isolation & purification
  • Benzofurans / metabolism*
  • Benzofurans / pharmacology
  • Binding Sites
  • Drug Resistance / genetics
  • Eukaryotic Initiation Factor-4A / chemistry
  • Eukaryotic Initiation Factor-4A / genetics
  • Eukaryotic Initiation Factor-4A / metabolism*
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Mutation
  • Plant Proteins / chemistry
  • Plant Proteins / genetics
  • Plant Proteins / metabolism
  • Protein Binding
  • Protein Biosynthesis* / drug effects
  • Protein Biosynthesis* / genetics
  • Protein Interaction Domains and Motifs
  • Protein Synthesis Inhibitors / chemistry
  • Protein Synthesis Inhibitors / isolation & purification
  • Protein Synthesis Inhibitors / metabolism*
  • Protein Synthesis Inhibitors / pharmacology
  • RNA / chemistry
  • RNA / metabolism*
  • Ribosomes / chemistry
  • Ribosomes / drug effects
  • Ribosomes / genetics
  • Ribosomes / metabolism*
  • Structure-Activity Relationship

Substances

  • Benzofurans
  • Plant Proteins
  • Protein Synthesis Inhibitors
  • Adenylyl Imidodiphosphate
  • RNA
  • rocaglamide
  • Eukaryotic Initiation Factor-4A