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Structure paper

TitleStructural and molecular basis of specialized translation mediated by the ribosome mRNA-binding channel.
Journal, issue, pagesNat Commun, Year 2026
Publish dateApr 29, 2026
AuthorsDavide Fraticelli / Disha Gajanan Hiregange / Benjamin Weiss / Ariel Ogran / Tal Havkin-Solomon / Irene Martinez Roman / Anat Bashan / Ada Yonath / Rivka Dikstein /
PubMed AbstractThe ribosome mRNA channel is central to translation, yet its role in regulatory mechanisms remains unclear. Using cryo-EM of human ribosomal complexes bound to Kozak and TISU mRNAs from wild-type (WT) ...The ribosome mRNA channel is central to translation, yet its role in regulatory mechanisms remains unclear. Using cryo-EM of human ribosomal complexes bound to Kozak and TISU mRNAs from wild-type (WT) and RPS26/eS26 mutant (RPS26dC) cells, we demonstrate that both RPS26/eS26 and mRNA adopt distinct conformations, explaining the opposing effects of RPS26dC on their activity. Translatome studies of WT and RPS26dC reveal AUG-context-dependent changes in 48S and 80S initiation complexes and slower scanning. Downregulated mRNAs are enriched for specific AUG-upstream nucleotides and a -1-cytosine contacting 18S rRNA G1207, an interaction lost in RPS26dC. Strongly affected transcripts include replication-dependent histones, which, despite short 5'UTRs and suboptimal Kozak, exhibit robust translation activity that is RPS26/eS26-dependent. We identify a translational enhancer in the H2B 5'UTR (-16 to -9) overlapping predicted RPS26/eS26-binding sites, with a distinct ribosome-bound conformation. Exploiting these features, we engineered a high-efficiency translational cassette with minimal leaky scanning. These findings underscore the role of the ribosome's mRNA channel in selective translation and its therapeutic potential.
External linksNat Commun / PubMed:42056121
MethodsEM (single particle)
Resolution2.5 - 3.0 Å
Structure data

EMDB-54265, PDB-9ru7:
WT-HEK 80S ribosome bound to Kozak mRNA (WT-Kozak)
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-54266, PDB-9ru8:
WT-HEK 80S ribosome bound to TISU mRNA (WT-TISU)
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-54267, PDB-9ru9:
RPS26dC HEK mutant 80S ribosome bound to Kozak mRNA (RPS26dC-Kozak)
Method: EM (single particle) / Resolution: 2.97 Å

EMDB-54268, PDB-9rua:
RPS26dC HEK mutant 80S ribosome bound to TISU mRNA (RPS26dC-TISU)
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-54269, PDB-9ruc:
WT-HEK 80S ribosome bound to H2B mRNA (WT-H2B)
Method: EM (single particle) / Resolution: 2.5 Å

Chemicals

ChemComp-K:
Unknown entry

ChemComp-MG:
Unknown entry

ChemComp-C:
CYTIDINE-5'-MONOPHOSPHATE

ChemComp-NA:
Unknown entry

ChemComp-ZN:
Unknown entry

ChemComp-HYG:
HYGROMYCIN B / antibiotic*YM

ChemComp-HOH:
WATER

ChemComp-SPD:
SPERMIDINE

ChemComp-SAC:
N-ACETYL-SERINE

ChemComp-AME:
N-ACETYLMETHIONINE

ChemComp-MET:
METHIONINE

ChemComp-ANM:
ANISOMYCIN / antibiotic*YM

Source
  • homo sapiens (human)
KeywordsRIBOSOME / 80S Ribosome / Kozak mRNA / Human / eS26 / WT-HEK / TISU mRNA / RPS26dC / H2B mRNA

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