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

• Published in: Molecular cell 2019-02, Vol.73 (4), p.738-748.e9
• Main Authors: Iwasaki, Shintaro, Iwasaki, Wakana, Takahashi, Mari, Sakamoto, Ayako, Watanabe, Chiduru, Shichino, Yuichi, Floor, Stephen N., Fujiwara, Koichi, Mito, Mari, Dodo, Kosuke, Sodeoka, Mikiko, Imataka, Hiroaki, Honma, Teruki, Fukuzawa, Kaori, Ito, Takuhiro, Ingolia, Nicholas T.
• Format: Article
• Language: English
• Subjects: 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; crystal structure; Drug Resistance - genetics; eIF4A; Eukaryotic Initiation Factor-4A - chemistry; Eukaryotic Initiation Factor-4A - genetics; Eukaryotic Initiation Factor-4A - metabolism; evolution; FMO; 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; Ribo-Seq; ribosome profiling; Ribosomes - chemistry; Ribosomes - drug effects; Ribosomes - genetics; Ribosomes - metabolism; RNA - chemistry; RNA - metabolism; Rocaglamide; sequence specificity; Structure-Activity Relationship; translation; X-ray
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2018.11.026

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. [Display omitted] •Crystallographic structure of the human eIF4A1⋅AMPPNP⋅RocA⋅polypurine RNA complex•Direct base recognition by RocA induces polypurine RNA selectivity on eIF4A1•Natural amino acid substitutions found in Aglaia eIF4As provide self-resistance to RocA 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.