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Title: Structural studies of proteins conferring nutrient uptake and drug efflux
Author: Qu, Feng
ISNI:       0000 0004 9356 9967
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2019
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Bacterial transporters play fundamental roles in nutrient acquisition and drug efflux. Determining the structures of these transport proteins is essential for understanding the mechanisms bacteria use to ensure cell survival. In E. coli, TauABCD is a taurine-sulfur assimilation system upregulated during conditions of sulfur starvation. The substrate-binding protein TauA is required for the initial step of taurine recognition followed by its delivery to the ABC transporter TauBC. In this work, structures of TauA in complex with taurine and three analogues have been determined. Structural comparison shows that the size of the binding site dictates substrate selectivity of TauA. Desolvation of the TauA binding site is likely to be a key determinant in the binding of taurine and its analogues. Under conditions of nutrient starvation, bacteria also produce and release antibacterial peptides like MccC7/C51. MccC7/C51 hijacks the ABC importer YejABEF to enter sensitive bacteria. However, the mechanism for MccC7/C51 internalisation and the physiological function of YejABEF have yet to be defined. In this work, the structure of YejA has been determined in a peptide-bound state, suggesting YejA is likely to be an oligopeptide-binding protein. Furthermore, interrogation of the bound peptide sequence provides a rationale for prodrug design of novel antibiotics. Finally, the AcrAB-TolC efflux system is a major reason for multidrug resistance in E. coli. AcrB is a major component of the system, responsible for energy transduction and substrate recognition. However, to date, no inhibitor against bacterial efflux pumps has been clinically licensed as a drug. Here, using a combination of transport and MIC assays, one compound has been highlighted as a potential AcrAB-TolC inhibitor. In addition, well diffracting crystals have been produced for AcrB in the conformation favouring ligand binding. These crystals were applied to the XChem fragment screening platform for ligand soaking. AcrB represents the first example of a membrane protein tested using this platform.
Supervisor: Beis, Konstantinos Sponsor: China Scholarship Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral