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

Year: 2026

Type: article

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.

Source: Nucleic Acids Research

DOI: 10.1093/nar/gkag761

Authors: Madhura N Paranjpe, Elodie C Leroy, Egor A Syroegin, Laurin Flemmich, Julia Thaler, Mélanie Gillard, Anthony Bougas, Georgia Kournoutou, George P Dinos, Thibaud T Renault, Ronald Micura, C Axel Innis, Yury S Polikanov

Institutions: University of Illinois Chicago, Centre National de la Recherche Scientifique, Université de Bordeaux, Inserm, Acides nucléiques: Régulations naturelles et artificielles, Universität Innsbruck, University of Patras

Language: English

Topic: RNA and protein synthesis mechanisms

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $3,992

Funders: U.S. Department of Energy, European Commission, Austrian Science Fund, National Institutes of Health, Office of Science, National Institute of General Medical Sciences, Office of Research Infrastructure Programs, National Institutes of Health, Argonne National Laboratory, H2020 European Research Council

OpenAlex ID: W7202272439