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Structural mechanism of FusB-mediated rescue from fusidic acid inhibition of protein synthesis

Author

Listed:
  • Adrián González-López

    (Uppsala University, BMC
    Uppsala University)

  • Xueliang Ge

    (Uppsala University, BMC)

  • Daniel S. D. Larsson

    (Uppsala University, BMC)

  • Carina Sihlbom Wallem

    (Scilifelab and University of Gothenburg)

  • Suparna Sanyal

    (Uppsala University, BMC)

  • Maria Selmer

    (Uppsala University, BMC
    Uppsala University)

Abstract

The antibiotic resistance protein FusB rescues protein synthesis from inhibition by fusidic acid (FA), which locks elongation factor G (EF-G) to the ribosome after GTP hydrolysis. Here, we present time-resolved single–particle cryo-EM structures explaining the mechanism of FusB-mediated rescue. FusB binds to the FA-trapped EF-G on the ribosome, causing large-scale conformational changes of EF-G that break interactions with the ribosome, tRNA, and mRNA. This leads to dissociation of EF-G from the ribosome, followed by FA release. We also observe two independent binding sites of FusB on the classical-state ribosome, overlapping with the binding site of EF-G to each of the ribosomal subunits, yet not inhibiting tRNA delivery. The affinity of FusB to the ribosome and the concentration of FusB in S. aureus during FusB-mediated resistance support that direct binding of FusB to ribosomes could occur in the cell. Our results reveal an intricate resistance mechanism involving specific interactions of FusB with both EF-G and the ribosome, and a non-canonical release pathway of EF-G.

Suggested Citation

  • Adrián González-López & Xueliang Ge & Daniel S. D. Larsson & Carina Sihlbom Wallem & Suparna Sanyal & Maria Selmer, 2025. "Structural mechanism of FusB-mediated rescue from fusidic acid inhibition of protein synthesis," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58902-3
    DOI: 10.1038/s41467-025-58902-3
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