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Title: Structural and functional studies of bacterial detoxification mechanisms
Author: Choudhury, Hassanul Ghani
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Bacterial multidrug resistance is a prominent issue with an ever-increasing amount of drugs becoming ineffective in treating bacterial infections. The elucidation of the 3D structure of bacterial resistance proteins has become extremely important in the development of new antimicrobials. Bacteria can sense external stimuli and regulate the expression of genes that can confer antibiotic resistance. Response regulators are capable of binding DNA both in their phosphorylated and unphosphorylated states, upregulating gene expression. The crystal structure of the unphosphorylated dimeric Escherichia coli BaeR in an intermediate state has been determined. One subunit of the dimer is in an 'active-like' conformation and the other in an inactive conformation. The dimer is formed by a domain swap, which is supported by our small angle X-ray scattering data. This structure provides a possible mechanism on how an unphosphorylated response regulator is capable of binding DNA. Bacteria can detoxify toxic chalcogens, selenium and tellurium, by methylation. The structure of the Escherichia coli TehB has been determined. From our functional analysis, TehB is capable of methylating different chalcogen oxyanions, making it a powerful detoxifying protein. Based on the structure, mutagenesis and kinetic data, we proposed a reaction mechanism for chalcogen detoxification. This data provides the first molecular understanding of the detoxification process of chalcogens by bacteria. In order to survive, certain bacteria under nutrient starved conditions produce antimicrobial peptides (e.g. bacteriocins and microcins) that target closely related species. They have dedicated ABC transporters to export the toxins out of the cells producing them. The crystal structure of the microcin J25 ABC exporter McjD has been determined. Our biochemical data show McjD has a high specificity towards its substrate. In addition, McjD adopts a new 'nucleotide-bound outward-occluded' conformation. Comparison with other ABC exporters has allowed us to propose an intermediate step in ABC exporter mechanism.
Supervisor: Iwata, So ; Beis, Konstantinos Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available