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

Adrián González-López, Xueliang Ge, Daniel S. D. Larsson, Carina Sihlbom Wallem, Suparna Sanyal and Maria Selmer ()
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Adrián González-López: Uppsala University, BMC
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

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58902-3

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