1. The Translation Inhibitor Rocaglamide Targets a Bimolecular Cavity between eIF4A and Polypurine RNA.
- Author
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Iwasaki S, Iwasaki W, Takahashi M, Sakamoto A, Watanabe C, Shichino Y, Floor SN, Fujiwara K, Mito M, Dodo K, Sodeoka M, Imataka H, Honma T, Fukuzawa K, Ito T, and Ingolia NT
- Subjects
- Adenylyl Imidodiphosphate chemistry, Adenylyl Imidodiphosphate metabolism, Aglaia chemistry, Aglaia genetics, Aglaia metabolism, Amino Acid Substitution, Benzofurans chemistry, Benzofurans isolation & purification, Benzofurans pharmacology, Binding Sites, Drug Resistance genetics, Eukaryotic Initiation Factor-4A chemistry, Eukaryotic Initiation Factor-4A genetics, HEK293 Cells, Humans, Models, Molecular, Molecular Structure, Mutation, Plant Proteins chemistry, Plant Proteins genetics, Plant Proteins metabolism, Protein Binding, Protein Interaction Domains and Motifs, Protein Synthesis Inhibitors chemistry, Protein Synthesis Inhibitors isolation & purification, Protein Synthesis Inhibitors pharmacology, RNA chemistry, Ribosomes chemistry, Ribosomes drug effects, Ribosomes genetics, Structure-Activity Relationship, Benzofurans metabolism, Eukaryotic Initiation Factor-4A metabolism, Protein Biosynthesis drug effects, Protein Biosynthesis genetics, Protein Synthesis Inhibitors metabolism, RNA metabolism, Ribosomes metabolism
- 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., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2019
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