Structural mechanism of FusB-mediated rescue from fusidic acid inhibition of protein synthesis.
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González-López A, Ge X, Larsson DSD, Sihlbom Wallem C, Sanyal S, Selmer M
Nat Commun 16 (1) 3693 [2025-04-18; online 2025-04-18]
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.
PubMed 40251147
DOI 10.1038/s41467-025-58902-3
Crossref 10.1038/s41467-025-58902-3
pmc: PMC12008383
pii: 10.1038/s41467-025-58902-3