AbstractWork 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: 188.8.131.52) 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: 184.108.40.206) 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.
|Date of Award||2013|
|Sponsors||Biotechnology and Biological Sciences Research Council|
|Supervisor||Bill Hunter (Supervisor)|
- Structural biology
- Drug discovery
- Type VI secretion
- 2C-methyl-D-erythritol 2,4-cyclodiphosphate
- Para-aminobenzoic acid
- 4-amino-4-deoxychorismate lyase
- fragment screening