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

Hironori Saito, Yuma Handa, Mingming Chen, Tilman Schneider-Poetsch, Yuichi Shichino, Mari Takahashi, Daniel Romo, Minoru Yoshida, Alois Fürstner, Takuhiro Ito, Kaori Fukuzawa and Shintaro Iwasaki ()
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Hironori Saito: Wako
Yuma Handa: Shinagawa
Mingming Chen: Wako
Tilman Schneider-Poetsch: Wako
Yuichi Shichino: Wako
Mari Takahashi: Tsurumi-ku
Daniel Romo: Baylor University
Minoru Yoshida: Wako
Alois Fürstner: Max-Planck-Institut für Kohlenforschung
Takuhiro Ito: Tsurumi-ku
Kaori Fukuzawa: Shinagawa
Shintaro Iwasaki: Wako

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51635-9

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