2. Academic Validation
  3. DMDA-PatA mediates RNA sequence-selective translation repression by anchoring eIF4A and DDX3 to GNG motifs

DMDA-PatA mediates RNA sequence-selective translation repression by anchoring eIF4A and DDX3 to GNG motifs

  • Nat Commun. 2024 Sep 2;15(1):7418. doi: 10.1038/s41467-024-51635-9.
Hironori Saito 1 2,  Yuma Handa 3,  Mingming Chen 1 2,  Tilman Schneider-Poetsch 4,  Yuichi Shichino 1,  Mari Takahashi 5,  Daniel Romo 6,  Minoru Yoshida 4 7,  Alois Fürstner 8,  Takuhiro Ito 5,  Kaori Fukuzawa 3 9,  Shintaro Iwasaki 10 11
Affiliations

Affiliations

  • 1 RNA Systems Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama, Japan.
  • 2 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan.
  • 3 School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Shinagawa, Tokyo, Japan.
  • 4 Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan.
  • 5 Laboratory for Translation Structural Biology, RIKEN Center for Biosystems Dynamics Research, Tsurumi-ku, Yokohama, Japan.
  • 6 Department of Chemistry & Biochemistry and Baylor Synthesis and Drug-Lead Discovery Laboratory, Baylor University, Waco, TX, USA.
  • 7 Office of University Professors, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
  • 8 Max-Planck-Institut für Kohlenforschung, Mülheim/Ruhr, Germany.
  • 9 Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
  • 10 RNA Systems Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama, Japan. shintaro.iwasaki@riken.jp.
  • 11 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan. shintaro.iwasaki@riken.jp.
PMID: 39223140 DOI: 10.1038/s41467-024-51635-9
Abstract

Small-molecule compounds that elicit mRNA-selective translation repression have attracted interest due to their potential for expansion of druggable space. However, only a limited number of examples have been reported to date. Here, we show that desmethyl desamino pateamine A (DMDA-PatA) represses translation in an mRNA-selective manner by clamping eIF4A, a DEAD-box RNA-binding protein, onto GNG motifs. By systematically comparing multiple eIF4A inhibitors by ribosome profiling, we found that DMDA-PatA has unique mRNA selectivity for translation repression. Unbiased Bind-n-Seq reveals that DMDA-PatA-targeted eIF4A exhibits a preference for GNG motifs in an ATP-independent manner. This unusual RNA binding sterically hinders scanning by 40S ribosomes. A combination of classical molecular dynamics simulations and quantum chemical calculations, and the subsequent development of an inactive DMDA-PatA derivative reveals that the positive charge of the tertiary amine on the trienyl arm induces G selectivity. Moreover, we identified that DDX3, another DEAD-box protein, is an alternative DMDA-PatA target with the same effects on eIF4A. Our results provide an example of the sequence-selective anchoring of RNA-binding proteins and the mRNA-selective inhibition of protein synthesis by small-molecule compounds.

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