Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.581880
Title: The FusB family of fusidic acid resistance proteins : structural and mechanistic insights
Author: Cox, Georgina
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2011
Availability of Full Text:
Access from EThOS:
Abstract:
The primary mechanism of resistance to the antibiotic fusidic acid (FA) in clinical strains of Staphylococcus aureus is expression of a FusB-type protein (usually FusB or FusC). These proteins bind elongation factor G (EF-G), the target of FA, and protect bacterial translation from FA-mediated inhibition. However, the interaction of these proteins with EF-G is poorly characterised, their structure has not been elucidated, and it is unknown how protection from FA is mediated. This thesis reports the first structure of a FusB-type protein, and begins to define the interaction between these proteins and EF-G. The 3D structure of FusC reveals a monomer composed of two distinct domains. The N-terminal domain comprises a four-helix bundle exhibiting similarity to existing protein structures. By contrast, the C-terminal domain forms a novel fold of helices and B-sheet with four conserved cysteine residues coordinating a central zinc ion. This region of FusB-type proteins was found to mediate a high-affinity interaction with the C-terminal domains of EF-G in vitro, yielding a complex with a 1: 1 stoichiometry. The protein-protein interaction occurs away from the FA binding site of EF-G, suggesting that FusB-type proteins do not mediate FA-resistance through direct steric hindrance of the interaction between FA and its target. Instead, FusB-type proteins interact with the portion of EF-G known to make contact with the inside of the ribosome. Owing to structural constraints, EF-G appears unable to simultaneously bind to FusB-type proteins and the ribosome. Based on these findings, a model of FusB-type resistance is proposed in which FusB-type proteins drive the release of frozen FA-EF-G-GDP complexes from the ribosome by competing for binding to EF-G.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.581880  DOI: Not available
Share: