Structural mechanism of FusB-mediated rescue from fusidic acid inhibition of protein synthesis
Year: 2025
Type: article
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.
Source: Nature Communications
Institutions: Uppsala University, University of Gothenburg
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: Eli Lilly and Company, Familjen Erling-Perssons Stiftelse, Diamond Light Source, Kempe Foundation, Sven och Lilly Lawskis Fond för Naturvetenskaplig Forskning, European Commission, Knut och Alice Wallenbergs Stiftelse, Vetenskapsrådet, Umeå Universitet, Uppsala Universitet, Stockholms Universitet, Science for Life Laboratory, Sahlgrenska Akademin, National Supercomputer Centre, Linköpings Universitet
Awards: Protein Synthesis in Bacteria: Mechanisms, Evolution and Application, G434337789, Mechanisms of Protein Synthesis in Bacteria and Protozoa with structure and function, Large scale, time- and cost-effective production and commercialization of human ribosome, G6095017884, Methylation in bacterial ribosome biogenesis and function - how, when and why?, G712881263, An Integrated Environment for Ribosome Research, Fundamental functions of S-adenosyl methionine in bacterial physiology and resistance
OpenAlex ID: W4409587725