{"doi":"10.1038/s41467-024-51635-9","title":"DMDA-PatA mediates RNA sequence-selective translation repression by anchoring eIF4A and DDX3 to GNG motifs","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.","journal":"Nature Communications","year":2024,"id":435717,"datarank":0.4202780227064112,"base_score":2.5649493574615367,"endowment":2.5649493574615367,"self_citation_contribution":0.38474240361923057,"citation_network_contribution":0.035535619087180594,"self_endowment_contribution":0.38474240361923057,"citer_contribution":0.035535619087180594,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":8,"citers_with_citation_signal":3,"citers_with_endowment":3,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9519,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE243312"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1192058,"name":"Yuma Handa","orcid":"0000-0001-8660-8487","position":1,"is_corresponding":false},{"id":1064457,"name":"Mingming Chen","orcid":"0000-0003-4453-1105","position":2,"is_corresponding":false},{"id":245405,"name":"Tilman Schneider‐Poetsch","orcid":"0009-0005-5829-1319","position":3,"is_corresponding":false},{"id":245404,"name":"Yuichi Shichino","orcid":"0000-0002-0093-1185","position":4,"is_corresponding":false},{"id":287606,"name":"Mari Takahashi","orcid":"0000-0002-9995-0019","position":5,"is_corresponding":false},{"id":342114,"name":"Daniel Romo","orcid":"0000-0003-3805-092X","position":6,"is_corresponding":false},{"id":245408,"name":"Minoru Yoshida","orcid":"0000-0002-4376-5674","position":7,"is_corresponding":false},{"id":579236,"name":"Alois Fürstner","orcid":"0000-0003-0098-3417","position":8,"is_corresponding":false},{"id":287609,"name":"Takuhiro Ito","orcid":"0000-0003-3704-5205","position":9,"is_corresponding":false},{"id":1151512,"name":"Kaori Fukuzawa","orcid":"0000-0001-5357-8250","position":10,"is_corresponding":false},{"id":17833,"name":"Shintaro Iwasaki","orcid":"0000-0001-7724-3754","position":11,"is_corresponding":false},{"id":236029,"name":"Hironori Saito","orcid":"0000-0001-9623-4132","position":0,"is_corresponding":true}],"reference_count":104,"raw_metadata":null,"created_at":"2026-07-19T02:00:08.103086Z","pmid":"39223140","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}