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PhD Studentship in Biomolecular Informatics and Protein Engineering
Department of Biochemistry, University of Cambridge in collaboration with Ipsen Bioinnovation
Project: Engineering of Botulinum Toxins with Enhanced Receptor Affinity
Supervisors: Professor Sir Tom Blundell and Dr David Ascher (University of Cambridge); Dr. Dina Anderson (Ipsen Bioinnovation LTD)
This 4 year PhD research project, due to start October 2016, is a collaboration between the University of Cambridge and Ipsen, a global biopharma company (http://www.ipsen.com). The doctoral student will be formally based at Cambridge in the group of Professor Blundell (http://www-cryst.bioc.cam.ac.uk/groups/blundell) and will also have a placement of three months or more at Ipsen, Abingdon, Oxon UK. The successful candidate will be awarded a doctorate from the University of Cambridge.
Background: Botulinum toxins (BoNT) comprise a family of extremely potent neurotoxins; this toxicity has been harnessed as a muscle relaxant for the treatment of a wide variety of debilitating diseases, particularly in the field of movement disorders. BoNT acts via entry into neurons and destructive cleavage of cellular proteins critical to vesicle fusion and neurotransmitter release at the neuromuscular junction. A dual receptor model has been proposed for BoNT binding to target neurons, first a low affinity ganglioside interaction followed by a higher affinity interaction with a protein receptor. A deeper understanding of the molecular nature of these interactions will facilitate the generation of modified BoNT proteins with novel characteristics and significant therapeutic potential.
Aims of the Project: This project is aimed principally at molecular characterisation of the interaction of BoNT/A with gangliosides with a potential for extending research into BoNT-protein receptor interactions, using a combination of computational, biochemical, and biophysical methods. In addition to the extension of existing computational tools to predict BoNT-ganglioside interactions, a key goal of this project is to generate novel BoNTs with improved receptor affinity. Specifically, the aims are to:
- Develop predictive computational models of BoNT-receptor interactions
- Develop novel biophysical assays to characterise BoNT-receptor interactions
- Design and evaluate binding properties of computationally predicted receptor-interacting modifications
Expected Outcomes: We expect that these studies will provide key insight to receptor binding properties. It is anticipated that this work will make significant contributions to the development of an engineered BoNT with novel receptor binding properties with increased therapeutic potential. In addition, it is expected that this work will generate a set of novel tools and methodologies which can be applied across all BoNTs.
The Candidate: The studentship offers the opportunity for a gifted individual to work on a problem of great significance, supported by two scientific groups of world standing. The candidate should have a first or upper second Bachelor of Science degree in biochemistry, chemistry, physics or a similar discipline. Practical experience in molecular biology, biochemistry, biophysics would be advantageous. A familiarity with molecular modelling, or computer programming ability, would be useful additional experience. The successful candidate will gain experience in a wide variety of computational drug-design methods, database searching tools, and statistical analysis methodology in a discipline which is of direct relevance to the pharmaceutical industries.
The 4 year project is fully funded by Ipsen with a stipend of ￡18,759 per annum. To be eligible for a full award, applicants must satisfy UK residency criteria (see http://www.bbsrc.ac.uk/web/FILES ... hip_eligibility.pdf).
Please submit a full CV and covering letter to Professor Sir Tom Blundell, Department of Biochemistry, university of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK. The Deadline for applications is the 31st March 2016
Apply: http://www-cryst.bioc.cam.ac.uk/groups/blundell
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