2 x 4-year PhD positions at UEA (Norwich, UK)

The following 2 x 4-year PhD position opportunities at the School of Pharmacy at the University of East Anglia (UEA), in Norwich are available.

 

(1st PhD position): How bacterial pathogens "sweeten" host proteins to avoid immunological responses: structural study of sugar transfer by bacterial virulence factors

(http://www.biodtp.norwichresearchpark.ac.uk/projects/project/how-bacterial-pathogens-sweeten-host-proteins-to-avoid-immunological-responses-structural-study-of-sugar-transfer-by-bacterial-virulence-factors-angulou18dtp)

 

Antimicrobial resistance is one of the biggest threats to global health. To reduce it, we must ensure that antibiotics are used only where appropriate. Accordingly, other non-antibiotic approaches are welcome, and a better understanding of the biology of bacterial infections is required. Pathogens such as Salmonella and E. coli inject virulence factors (effectors) to suppress antimicrobial host responses, to promote colonisation. The NleB effector is highly conserved among pathogens. It transfers GlcNAc sugar residues to host proteins (GAPDH, FADD, TRADD), a "sweet tag” that inhibits NF-kB activation and apoptosis of infected cells, blocking major antimicrobial host responses.

 

In this project, we will use advanced NMR spectroscopy, molecular modelling (protein-ligand docking, long accelerated molecular dynamics simulations), and other biophysical techniques (ITC) to unveil the structural features at atomic detail of the molecular recognition of host proteins by the bacterial effectors NleB1, SseK1, and SseK2. Members of this conserved family modify different host proteins and exhibit distinct modes of action to suppress host responses, but, interestingly, they differ only in a very small number of amino acids. We will try to rationalise the molecular basis of their exquisite selectivity, and the impact of sugar transfer on the interactions with other host proteins such as TRAF2.

 

(2nd PhD position): Ginsenosides and P2X receptors: natural resources for microbial killing: understanding their molecular basis using computational, biological and biophysical approaches

 

(http://www.biodtp.norwichresearchpark.ac.uk/projects/project/ginsenosides-and-p2x-receptors-natural-resources-for-microbial-killing-understanding-their-molecular-basis-using-computational-biological-and-biophysical-approaches-stokesu18dtp1)

 

Purinergic P2X receptors are ligand-gated ion channels involved in many physiological and pathophysiological processes. A number of selective pharmacological agents for P2X7 receptors have been discovered, however mapping drug binding sites is still in its infancy for this family of receptors. Ginsenosides are known to act as positive allosteric modulators at P2X7 receptors, making the receptor more sensitive to its ligand, ATP. The Stokes group in the School of Pharmacy at UEA is interested in studying the biological effects of ginsenoside modulation of P2X7 in immune cells and whether this action may underlie some of the reported immune boosting actions of ginsenosides in vivo.

 

In close collaboration with the Angulo group, this project will use a variety of 3D molecular modelling and molecular dynamics techniques to map out the molecular binding site for ginsenosides on P2X receptors. The binding site will be verified by biological experiments using a site-directed mutagenesis approach and measurements of ion channel activity. We will also develop a novel biophysical approach for measuring drug binding using saturation transfer difference (STD) NMR spectroscopy.

 

Both projects are excellent opportunities for first class student training in a multidisciplinary environment. The students will be trained in advanced NMR spectroscopy, modelling, recombinant protein production, Isothermal Titration Calorimetry, fluorescent assays and molecular biology. UEA and NRP also provide training in research techniques, data handling, and transferable skills in paper and grant writing and presentation skills.

 

Recruitment to the NRPDTP is now open. The deadline for applications is the 27th November 2017.

 

Interested strong candidates can contact Dr. Jesus Angulo (j.angulo@uea.ac.uk).

 

 

Dr Jesus Angulo | Senior Lecturer in NMR Spectroscopy | School of Pharmacy

1.47 CAP Building, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ

(+44 (0)1603 597155| * j.angulo@uea.ac.uk