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Peer-reviewedCC BY 4.0ACS Central Science

Altering the E. coli Ribosome Exit Tunnel to Improve Consecutive Incorporation of Challenging Monomers

  • Alexandra D. Kent1
  • Chandrima Majumdar1
  • Katelyn A. Fitzgerald1
  • Alexander C. Solivan1
  • Martina Boga de Teresa1
  • Jessica T. Vance1
  • Alanna Schepartz1,2,3
  • Jamie H. D. Cate1,4
4 affiliations
  1. 1University of California , , , ,
  2. 2Chan Zuckerberg Biohub , , ,
  3. 3Arc Institute , , ,
  4. 4Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory , , ,
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Abstract

Ribosomes are capable of incorporating a wide array of natural and unnatural monomers into growing polymer chains, but can be stalled by monomers with constrained or non-natural backbones. Here we evaluate whether monomer-dependent ribosome stalling can be alleviated by structure-guided mutations to 23S rRNA within the exit tunnel. Escherichia coli (E. coli) ribosomes harboring an A2062U mutation are as active as wild type (WT) ribosomes when translating nonproline sequences and up to 10-fold more active when translating sequences containing three or four consecutive proline residues. High-resolution cryo-EM structures of WT and A2062U mutant ribosomes containing a polyproline nascent chain reveal that the A2062U mutation relieves an exit tunnel constriction to better accommodate a conformationally restricted peptide chain. A2062U mutant ribosomes also improve translation of sequences containing multiple, consecutive β2-hydroxy acids. These results provide a mechanistic basis for engineering the E. coli ribosome for improved translation of genetically encoded polymers with novel backbones.

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Cite

BibTeXRIS
BibTeX
@article{kent2026altering,
  title = {{Altering the E. coli Ribosome Exit Tunnel to Improve Consecutive Incorporation of Challenging Monomers}},
  author = {Alexandra D. Kent and Chandrima Majumdar and Katelyn A. Fitzgerald and Alexander C. Solivan and Martina Boga de Teresa and Jessica T. Vance and Alanna Schepartz and Jamie H. D. Cate},
  journal = {ACS Central Science},
  year = {2026},
  month = nov,
  doi = {10.1021/acscentsci.6c01225},
  url = {https://pubs.acs.org/acscii/article/doi/10.1021/acscentsci.6c01225/5462358/Altering-the-E-coli-Ribosome-Exit-Tunnel-to},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Altering the E. coli Ribosome Exit Tunnel to Improve Consecutive Incorporation of Challenging Monomers
AU  - Alexandra D. Kent
AU  - Chandrima Majumdar
AU  - Katelyn A. Fitzgerald
AU  - Alexander C. Solivan
AU  - Martina Boga de Teresa
AU  - Jessica T. Vance
AU  - Alanna Schepartz
AU  - Jamie H. D. Cate
PY  - 2026
DA  - 2026/11/02
JO  - ACS Central Science
DO  - 10.1021/acscentsci.6c01225
UR  - https://pubs.acs.org/acscii/article/doi/10.1021/acscentsci.6c01225/5462358/Altering-the-E-coli-Ribosome-Exit-Tunnel-to
AB  - Ribosomes are capable of incorporating a wide array of natural and unnatural monomers into growing polymer chains, but can be stalled by monomers with constrained or non-natural backbones. Here we evaluate whether monomer-dependent ribosome stalling can be alleviated by structure-guided mutations to 23S rRNA within the exit tunnel. Escherichia coli (E. coli) ribosomes harboring an A2062U mutation are as active as wild type (WT) ribosomes when translating nonproline sequences and up to 10-fold more active when translating sequences containing three or four consecutive proline residues. High-resolution cryo-EM structures of WT and A2062U mutant ribosomes containing a polyproline nascent chain reveal that the A2062U mutation relieves an exit tunnel constriction to better accommodate a conformationally restricted peptide chain. A2062U mutant ribosomes also improve translation of sequences containing multiple, consecutive β2-hydroxy acids. These results provide a mechanistic basis for engineering the E. coli ribosome for improved translation of genetically encoded polymers with novel backbones.
SN  - 2374-7943
SN  - 2374-7951
ER  -