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- Title
DMDA-PatA mediates RNA sequence-selective translation repression by anchoring eIF4A and DDX3 to GNG motifs.
- Authors
Saito, Hironori; Handa, Yuma; Chen, Mingming; Schneider-Poetsch, Tilman; Shichino, Yuichi; Takahashi, Mari; Romo, Daniel; Yoshida, Minoru; Fürstner, Alois; Ito, Takuhiro; Fukuzawa, Kaori; Iwasaki, Shintaro
- 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. Here the authors report that DMDA-PatA, an anti-tumor compound, functions as a mRNA-selective translational inhibitor. This drug clamps the target eIF4A and DDX3 RNA-binding proteins on the GNG RNA motif, providing steric hindrance for scanning ribosomes.
- Subjects
RNA-binding proteins; MOLECULAR dynamics; STERIC hindrance; PROTEIN synthesis; TERTIARY amines
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-51635-9