RRC ID 56644
Author 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, Ingolia NT.
Title The Translation Inhibitor Rocaglamide Targets a Bimolecular Cavity between eIF4A and Polypurine RNA.
Journal Mol Cell
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.
Volume 73(4)
Pages 738-748.e9
Published 2019-2-21
DOI 10.1016/j.molcel.2018.11.026
PII S1097-2765(18)30996-1
PMID 30595437
PMC PMC6386617
MeSH 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
IF 14.548
Times Cited 24
DNA material pET47-eIF4A1-19-406 (RDB17294) pcDNA5/FRT/TO-SBP-eIF4A1 Phe163Leu (RDB17296) pcDNA5/FRT/TO-SBP-eIF4A1 Ile199Met (RDB17297) pcDNA5/FRT/TO-SBP-eIF4A1 Phe163Leu-Ile199Met (RDB17298) pColdI-eIF4A1 WT (RDB17299) pColdI-eIF4A1 Phe163Leu (RDB17300) pColdI-eIF4A1 Ile199Met (RDB17301) pColdI-eIF4A1 Phe163Leu-Ile199Met (RDB17302) pColdI-Ao-eIF4A-1 iso2 (RDB17303) pHISMBP-eIF4A1-NTD (Phe163Leu-Ile199Met) (RDB17305)