Sparsomycin inhibits translation through a conserved mechanism across all domains of life

Abstract

Sparsomycin (SPA) is a broad-spectrum inhibitor of protein synthesis with activity across all three domains of life. Although SPA has long been known to target the ribosomal peptidyl transferase center (PTC), previous structural studies suggested that SPA binds differently to bacterial ribosomes compared to their archaeal and eukaryotic counterparts—an unexpected conclusion given the high evolutionary conservation of the ribosomal catalytic center. Here, we show that SPA inhibits a majority of elongation-competent bacterial ribosomal complexes and present X-ray crystal structures of Thermus thermophilus 70S ribosomes stalled by SPA at the initiation and early elongation stages of translation. These structures reveal that SPA binds to the bacterial ribosome in a manner essentially identical to that observed in archaeal and eukaryotic ribosomes, establishing a unified structural mechanism of SPA action across all domains of life. In this conserved binding mode, SPA occupies the A-site cleft of the PTC and forms an extensive network of interactions with universally conserved ribosomal RNA nucleotides and the CCA-end of the P-site transfer RNA (tRNA), thereby stabilizing the peptidyl-tRNA substrate while sterically blocking accommodation of an incoming aminoacyl-tRNA. By clarifying the mode of action of SPA on the bacterial ribosome, our work provides a structural framework for the rational design of SPA derivatives with improved potency and bacterial specificity.

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BibTeX RIS

BibTeX

@article{paranjpe2026sparsomycin,
  title = {{Sparsomycin inhibits translation through a conserved mechanism across all domains of life}},
  author = {Madhura Paranjpe and Elodie Leroy and Egor Syroegin and Laurin Flemmich and Julia Thaler and Mélanie Gillard and Anthony Bougas and Georgia Kournoutou and George Dinos and Thibaud Renault and Ronald Micura and C Axel Innis and Yury Polikanov},
  journal = {Nucleic Acids Research},
  year = {2026},
  month = oct,
  doi = {10.1093/nar/gkag761},
  url = {https://hal.science/hal-05750496v1},
  note = {CC BY-NC 4.0},
}

RIS

TY  - JOUR
TI  - Sparsomycin inhibits translation through a conserved mechanism across all domains of life
AU  - Madhura Paranjpe
AU  - Elodie Leroy
AU  - Egor Syroegin
AU  - Laurin Flemmich
AU  - Julia Thaler
AU  - Mélanie Gillard
AU  - Anthony Bougas
AU  - Georgia Kournoutou
AU  - George Dinos
AU  - Thibaud Renault
AU  - Ronald Micura
AU  - C Axel Innis
AU  - Yury Polikanov
PY  - 2026
DA  - 2026/10/08
JO  - Nucleic Acids Research
DO  - 10.1093/nar/gkag761
UR  - https://hal.science/hal-05750496v1
AB  - Sparsomycin (SPA) is a broad-spectrum inhibitor of protein synthesis with activity across all three domains of life. Although SPA has long been known to target the ribosomal peptidyl transferase center (PTC), previous structural studies suggested that SPA binds differently to bacterial ribosomes compared to their archaeal and eukaryotic counterparts—an unexpected conclusion given the high evolutionary conservation of the ribosomal catalytic center. Here, we show that SPA inhibits a majority of elongation-competent bacterial ribosomal complexes and present X-ray crystal structures of Thermus thermophilus 70S ribosomes stalled by SPA at the initiation and early elongation stages of translation. These structures reveal that SPA binds to the bacterial ribosome in a manner essentially identical to that observed in archaeal and eukaryotic ribosomes, establishing a unified structural mechanism of SPA action across all domains of life. In this conserved binding mode, SPA occupies the A-site cleft of the PTC and forms an extensive network of interactions with universally conserved ribosomal RNA nucleotides and the CCA-end of the P-site transfer RNA (tRNA), thereby stabilizing the peptidyl-tRNA substrate while sterically blocking accommodation of an incoming aminoacyl-tRNA. By clarifying the mode of action of SPA on the bacterial ribosome, our work provides a structural framework for the rational design of SPA derivatives with improved potency and bacterial specificity.
SN  - 0305-1048
SN  - 1362-4962
ER  -

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