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bioRxiv · 10.1101/2024.08.30.610483

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

Gonzalez Lopez, A.·Ge, X.·Larsson, D. S. D.·Sanyal, S.·Selmer, M.
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Abstract

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 ribosome interactions. 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. 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.

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Gonzalez Lopez, A., Ge, X., Larsson, D. S. D., Sanyal, S., Selmer, M.. 2024-08-31. Structural mechanism of FusB-mediated rescue from fusidic acid inhibition of protein synthesis. https://doi.org/10.1101/2024.08.30.610483

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