Download MendeleyStructural mechanism of FusB-mediated rescue from fusidic acid inhibition of protein synthesis.
Gonzalez-Lopez, A., Ge, X., Larsson, D.S.D., Sihlbom Wallem, C., Sanyal, S., Selmer, M.(2025) Nat Commun 16: 3693-3693
- PubMed: 40251147
- DOI: https://doi.org/10.1038/s41467-025-58902-3
- Primary Citation of Related Structures:
9GHA, 9GHB, 9GHC, 9GHD, 9GHE, 9GHF, 9GHG, 9GHH - PubMed 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.
Organizational Affiliation:
Department of Cell and Molecular Biology, Uppsala University, BMC, Uppsala, Sweden.
