SWDTP studentship and CASE studentship position, Bristol, UK

1)      Industrial CASE award.

Application of Fast NMR data Acquisition Methods for Information Rich Fragment Screening of GPCRs. With Professor Matthew Crump (University of Bristol), Dr Richard Sessions (University of Bristol) and Dr Richard Taylor (UCB Pharma, Slough, UK).

SWDTP webpage and link to applications.
FindaPhD link: http://www.findaphd.com/search/ProjectDetails.aspx?PJID=67707&LID=174

The aim of this Ph.D. studentship at Bristol University is, therefore, to enable rapid delivery of information rich multidimensional NMR data to confirm the location of fragment ligand binding, using minimal amounts of protein but without compromising the data quality. This will be achieved by a combination of computational modelling to prioritise the most promising chemical leads and advanced mathematical non-uniform data sampling and reconstruction methods applied to the acquisition and processing of NMR data recorded using state-of the- art low volume NMR technology for samples of fragment ligand mixed with proteins of therapeutic interest in drug discovery. NMR data will be collected on a Bruker 700 MHz spectrometer located in the School of Chemistry at UoB and equipped with a 1.7 mm cryoprobe using only 35 microlitres of sample. Purchase of this instrument was part funded by UCB. The computational aspects of the project will then be extended to using this NMR data to further refine the positioning of this fragment in the protein binding site and will be undertaken in collaboration with the School of Biochemistry at UoB (Sessions). The studentship will also benefit from access to UCB’s extensive Structural Biology infrastructure, including NMR facilities, via the industrial placement component of the project.

2). SWDTP studentship.

NMR and X-ray studies to probe whether the extracellular domains of IGF2R are Nature’s answer to a scalable ligand binding platform?

SWDTP webpage and link to applications.

FindaPhD link: http://www.findaphd.com/search/ProjectDetails.aspx?PJID=67670&LID=174
Nature’s ability to use an existing blue-print or design and evolve it to serve a new, perhaps unexpected purpose, is a continuing source of fascination and has led to the rich and diverse biology we observe around us. This process scales from the molecular level where changes to proteins might lead to new biochemistry that drives the huge diversity we see at the macroscopic scale. One such example of this process in action can be found in proteins that have a similar three-dimensional shape but are equipped with special hotspots that can adapt to bind or capture different molecules, which may themselves be proteins or simpler chemicals. This is exemplified in a receptor molecule that we study called insulin growth factor 2 receptor (IGF2R) (Crump & Hassan and co-workers 2012, Science 238, 1209-1213.). This 300 kDa protein contains fifteen structurally similar domains but with very different sets of surface loops that have evolved to bind a variety of ligands ranging from simple sugars (mono- and disaccharides) up to larger proteins such as Insulin Growth Factor-2 (see figure). Our fundamental interest in this receptor stems from its anti-tumour activity and role in several cancers. The diversity of its ligands is unprecedented and reveals the sophistication of this underlying scaffold and the potential for use in biotechnology and biological applications. We therefore aim to explore the potential of easily produced domain11 for evolving to bind carbohydrates, phosphodiesters and many other ligands of choice. There has been relatively little focus so far on evolving scaffolds to target small molecules but this is changing however and there have been recent reports of using engineered anticalines for binding the well-characterized immunological hapten fluorescein with many biological applications (e.g. imaging).
Jointly supervised with Dr Paul Race (Biochemistry, UoB), collaborator Professor Bass Hassan (clinical oncologist, Oxford).

For further information email matt.crump@bristol.ac.uk