9spi
CRYO-EM STRUCTURE OF HUMAN 80S RIBOSOME WITH A/P/E-SITE TRNA AND MRNA CONTAINING URIDINE
Structural highlights
FunctionRL3_HUMAN The L3 protein is a component of the large subunit of cytoplasmic ribosomes. Publication Abstract from PubMedThe considerable success of mRNA vaccines against SARS-CoV-2 has underscored the potential of synthetic mRNA as a transformative biomedical technology(1). A critical feature of this approach is the incorporation of the modified nucleoside N(1)-methylpseudouridine (m(1)Psi), which enhances antigen expression while reducing immunogenicity(2-5). However, a comprehensive understanding of how m(1)Psi influences translation remains incomplete. Here we use ribosome profiling at the subcodon resolution to show that m(1)Psi increases ribosome density on synthetic mRNAs, leading to higher protein production independent of innate immune activation or eIF2alpha phosphorylation. We find that m(1)Psi directly slows ribosome movement in defined sequence contexts while simultaneously promoting translation initiation. Structural studies using cryo-electron microscopy reveal that m(1)Psi alters interactions within the ribosomal decoding centre, providing a mechanistic basis for slowed elongation. Furthermore, by introducing synonymous recoding that disrupts the modification-mediated changes in elongation, we show that the m(1)Psi-dependent enhancement of protein output is modulated by codon composition, and that m(1)Psi impact is strongest in mRNAs containing non-optimal codons with uridines at the wobble position. Together, these findings demonstrate that m(1)Psi directly modulates translation dynamics, thereby increasing protein yield from synthetic mRNAs in specific sequence contexts. N(1)-Methylpseudouridine directly modulates translation dynamics.,Rozman B, Broennimann K, Rajan KS, Nachshon A, Saha C, Arazi T, Mohan V, Geiger T, Wollner CJ, Richner JM, Westhof E, Yonath A, Bashan A, Stern-Ginossar N Nature. 2026 Jan 14. doi: 10.1038/s41586-025-09945-5. PMID:41535458[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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