Download MendeleyThe Translation Inhibitor Rocaglamide Targets a Bimolecular Cavity between eIF4A and Polypurine RNA.
Iwasaki, S., Iwasaki, W., Takahashi, M., Sakamoto, A., Watanabe, C., Shichino, Y., Floor, S.N., Fujiwara, K., Mito, M., Dodo, K., Sodeoka, M., Imataka, H., Honma, T., Fukuzawa, K., Ito, T., Ingolia, N.T.(2019) Mol Cell 73: 738
- PubMed: 30595437
- DOI: https://doi.org/10.1016/j.molcel.2018.11.026
- Primary Citation of Related Structures:
5ZC9 - PubMed 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.
Organizational Affiliation:
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; RNA Systems Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama 351-0198, Japan; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 277-8561, Japan. Electronic address: [email protected].
