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Title: Structural studies to inform antimicrobial drug discovery and the basis of immunity against T6 effectors
Author: O'Rourke, Patrick
Awarding Body: University of Dundee
Current Institution: University of Dundee
Date of Award: 2013
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Work presented in this thesis is in two parts. Part one: The X-ray crystal structures of potential antimicrobial drug targets. The protein IspF (2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase, EC: from two pathogens (Burkholderia cenocepacia and Plasmodium falciparum) has been investigated. IspF is an enzyme of isoprenoid-precursor biosynthesis and is considered to be a potential drug target. The results of structural and fragment-screening efforts presented here inform early stage drug discovery efforts. The structure of the PabC protein (4-amino-4-deoxychorismate lyase, EC: from the Gram-negative pathogen Pseudomonas aeruginosa was also determined. PabC is involved in the production of para-aminobenzoic acid on the path to folate. Comparisons with previously solved PabC structures identified a spatially conserved tyrosine residue in the active site and suggest that a re-evaluation of a published mechanism is warranted. Part two: Immunity proteins in the Gram-negative Type VI secretion system. The X-ray crystal structures of the proteins Rap1a and Rap2a from Serratia marcescens, inhibitors of the peptidoglycan amidase toxins secreted by some Gram-negative bacteria employing the Type VI secretion pathway, were determined by molecular replacement and analysed.
Supervisor: Hunter, William Sponsor: Biotechnology and Biological Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: X-ray ; Crystallography ; Structural biology ; Drug discovery ; Antimicrobial ; Type VI secretion ; IspF ; PabC ; 2C-methyl-D-erythritol 2,4-cyclodiphosphate ; Para-aminobenzoic acid ; 4-amino-4-deoxychorismate lyase ; fragment screening