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


Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
02 Sep 2024
Historique:
received: 13 10 2023
accepted: 11 08 2024
medline: 3 9 2024
pubmed: 3 9 2024
entrez: 2 9 2024
Statut: epublish

Résumé

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.

Identifiants

pubmed: 39223140
doi: 10.1038/s41467-024-51635-9
pii: 10.1038/s41467-024-51635-9
doi:

Substances chimiques

DEAD-box RNA Helicases EC 3.6.4.13
Eukaryotic Initiation Factor-4A EC 2.7.7.-
DDX3X protein, human EC 3.6.1.-
pateamine A 0
RNA, Messenger 0
EIF4A1 protein, human 0
Epoxy Compounds 0
Thiazoles 0
Macrolides 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

7418

Subventions

Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : JP23H02415
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : JP23H00095
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : JP23K05648
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : JP19H05640
Organisme : Ministry of Education, Culture, Sports, Science and Technology (MEXT)
ID : JP20H05784
Organisme : Ministry of Education, Culture, Sports, Science and Technology (MEXT)
ID : JP24H02307
Organisme : Ministry of Education, Culture, Sports, Science and Technology (MEXT)
ID : JP21H05734
Organisme : Ministry of Education, Culture, Sports, Science and Technology (MEXT)
ID : JP23H04268
Organisme : Ministry of Education, Culture, Sports, Science and Technology (MEXT)
ID : JP18H05503
Organisme : Ministry of Education, Culture, Sports, Science and Technology (MEXT)
ID : JP21H05281
Organisme : Japan Agency for Medical Research and Development (AMED)
ID : JP23gm1410001
Organisme : Japan Agency for Medical Research and Development (AMED)
ID : JP23gm1410001
Organisme : MEXT | RIKEN
ID : Pioneering Projects
Organisme : MEXT | RIKEN
ID : Incentive Research Projects
Organisme : MEXT | RIKEN
ID : Pioneering Projects
Organisme : MEXT | RIKEN
ID : Pioneering Projects

Informations de copyright

© 2024. The Author(s).

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Auteurs

Hironori Saito (H)

RNA Systems Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama, Japan.
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan.

Yuma Handa (Y)

School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Shinagawa, Tokyo, Japan.

Mingming Chen (M)

RNA Systems Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama, Japan.
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan.

Tilman Schneider-Poetsch (T)

Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan.

Yuichi Shichino (Y)

RNA Systems Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama, Japan.

Mari Takahashi (M)

Laboratory for Translation Structural Biology, RIKEN Center for Biosystems Dynamics Research, Tsurumi-ku, Yokohama, Japan.

Daniel Romo (D)

Department of Chemistry & Biochemistry and Baylor Synthesis and Drug-Lead Discovery Laboratory, Baylor University, Waco, TX, USA.

Minoru Yoshida (M)

Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan.
Office of University Professors, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.

Alois Fürstner (A)

Max-Planck-Institut für Kohlenforschung, Mülheim/Ruhr, Germany.

Takuhiro Ito (T)

Laboratory for Translation Structural Biology, RIKEN Center for Biosystems Dynamics Research, Tsurumi-ku, Yokohama, Japan.

Kaori Fukuzawa (K)

School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Shinagawa, Tokyo, Japan.
Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.

Shintaro Iwasaki (S)

RNA Systems Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama, Japan. shintaro.iwasaki@riken.jp.
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan. shintaro.iwasaki@riken.jp.

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