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

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.
Shintaro Iwasaki 1,  Wakana Iwasaki 2,  Mari Takahashi 2,  Ayako Sakamoto 2,  Chiduru Watanabe 3,  Yuichi Shichino 4,  Stephen N Floor 5,  Koichi Fujiwara 6,  Mari Mito 4,  Kosuke Dodo 7,  Mikiko Sodeoka 7,  Hiroaki Imataka 8,  Teruki Honma 3,  Kaori Fukuzawa 9,  Takuhiro Ito 10,  Nicholas T Ingolia 11
Affiliations

Affiliations

  • 1 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: shintaro.iwasaki@riken.jp.
  • 2 Laboratory for Translation Structural Biology, RIKEN Center for Biosystems Dynamics Research, Tsurumi-ku, Yokohama 230-0045, Japan; Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, Tsurumi-ku, Yokohama 230-0045, Japan.
  • 3 Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, Tsurumi-ku, Yokohama 230-0045, Japan; Laboratory for Structure-Based Molecular Design, RIKEN Center for Biosystems Dynamics Research, Tsurumi-ku, Yokohama 230-0045, Japan.
  • 4 RNA Systems Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama 351-0198, Japan.
  • 5 Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 6 Synthetic Organic Chemistry Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama 351-0198, Japan.
  • 7 Synthetic Organic Chemistry Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama 351-0198, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Wako, Saitama 351-0198, Japan; RIKEN Center for Sustainable Resource Science, Wako, Saitama 351-0198, Japan.
  • 8 Graduate School of Engineering, University of Hyogo, Himeji, Hyogo 671-2201, Japan.
  • 9 School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Shinagawa, Tokyo 142-8501, Japan.
  • 10 Laboratory for Translation Structural Biology, RIKEN Center for Biosystems Dynamics Research, Tsurumi-ku, Yokohama 230-0045, Japan; Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, Tsurumi-ku, Yokohama 230-0045, Japan. Electronic address: takuhiro.ito@riken.jp.
  • 11 Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: ingolia@berkeley.edu.
PMID: 30595437 DOI: 10.1016/j.molcel.2018.11.026
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.

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