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

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.

Authors

Institutions

Publication Details

Journal
Nature Communications
Published
2024-09-02
DOI
https://doi.org/10.1038/s41467-024-51635-9
Citations
10
Primary Topic
RNA and protein synthesis mechanisms
Type
article
Field-Weighted Citation Impact
2.34

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Daniel Romo, Mari Takahashi, Minoru Yoshida, Shintaro Iwasaki et al.
10 citations
Nature Communications
RNA and protein synthesis mechanisms
2.34
article

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

Daniel Romo, Mari Takahashi, Minoru Yoshida, Shintaro Iwasaki, Tilman Schneider‐Poetsch, Alois Fürstner, Yuma Handa, Mingming Chen, Takuhiro Ito, Hironori Saito, Kaori Fukuzawa, Yuichi Shichino
article en
10 citations

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.

Nature CommunicationsVol. 15(1)
Pioneer (United States) (US), Baylor University (US), Hoshi University (JP), Max-Planck-Institut für Kohlenforschung (DE), RIKEN Center for Sustainable Resource Science (JP), Pioneer (Japan) (JP), RIKEN (JP), RIKEN Center for Biosystems Dynamics Research (JP), The University of Tokyo (JP), The University of Osaka (JP)
Japan Agency for Medical Research and Development, Ministry of Education, Culture, Sports, Science and Technology, National Institutes of Health, Japan Society for the Promotion of Science, RIKEN, National Institute of General Medical Sciences
Openalex Percentile: Top 11%
RNA and protein synthesis mechanisms
2.34
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.