Thursday, April 30, 2009

PhD Positions Available

PhD Scholarships available in Structural Biology

Applications are invited for PhD scholarships in the following areas:

The structure of insecticidal toxins from Yersinia entomophaga.
(Dr. Shaun Lott, Dr Mark Hurst, Biocontrol and Biosecurity, AgResearch)

The insecticidal tc toxins produced by a number of bacteria form large (~2.5MDa) complexes, where the assembly of up to seven proteins are required to show full insecticidal activity. The general architecture of these complexes has previously been established using single-particle EM analysis, but the structural details of the complexes, and their mode of action, remain obscure. This project aims to elucidate the structures and functions of components of the tc toxin complex from the bacterium Yersinia entomophaga.

Drug targets from M. tuberculosis.
(Dr. Shaun Lott, Professor Ted Baker)

We have recently solved the structure of several enzymes known to be essential for the bacterium to cause disease, including anthranilate phosphoribosyl transferase (AnPRT; TrpD), the enzyme which catalyses the second committed step in tryptophan biosynthesis, isopropylmalate synthase (IPMS; LeuA), the enzyme which catalyses the first committed step in leucine biosynthesis, salicylate synthase (MbtI) which catalyses the production of salicylate, essential for the production of the siderophore mycobactin, and others. Through a combination of in silico modelling and in vitro assay, we have identified a set of weak AnPRT inhibitors, and are embarking on the structure-guided synthesis of more potent versions. We plan to use a similar approach with the other enzymes also, with the intention of producing useful anti-mycobacterial agents for the future.

Host lipid-induced transcriptional regulation in M. tuberculosis.
(Dr. Shaun Lott, Dr Sharon Kendall, Royal Veterinary College, London)

We have recently showed that the essential transcriptional regulator KstR, which has previously been implicated in pathogenesis, directly controls the expression of many lipid metabolism genes in M. tuberculosis. Additionally, a similar transcriptional regulator, KstR2, has also been identified to control a smaller regulon. KstR and KstR2 both belong to the TetR family of transcriptional regulators, and our hypothesis is that the activation of KstR and/or KstR2 is triggered by lipid ligands derived from the human host, triggering bacterial adaptation to the intracellular environment. We are aiming to structurally and functionally characterise these transcription factors to discover more about their mode of action.

Novel proteins from Orf virus.
(Dr. Chris Squire, Professor Ted Baker, Prof. Andrew Mercer, Virus Research Unit, Otago University)

Orf virus is an animal virus, and a member of the poxvirus family. Its genome sequence shows that in addition to the genes required for replication and assembly, it encodes genes for a large number of novel proteins that appear to have no counterparts in other organisms. We believe that many of these proteins are involved in infection, or in immune avoidance (by mimicking components of the host immune system). Some of these have potential therapeutic applications. We have carried out a preliminary bioinformatic survey, and identified a subset of these proteins that we predict to have important functions, and well defined structures. The aim is to express and purify the proteins, test their predicted functions and determine their 3D structures by X-ray crystallography.

These scholarships are funded by research grants from the NZ Foundation for Research, Science & Technology, and include University Fees, working expenses and a stipend of NZ$25,000 p/a. Candidates should have a First or Upper Second Class Honours or Masters Degree or equivalent, and have a strong interest in using protein structure to elucidate biological function.

Applicants should write to Dr Shaun Lott ( or Prof. Ted Baker ( in the first instance, enclosing a CV and an academic transcript, citing reference AGNRF1, by May 15th 2009. Informal inquiries are welcomed at the same addresses.

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