About the Project
Cu/Zn binding superoxide dismutase is a homo-dimeric protein with an intra-subunit disulphide bond. This protein is responsible for converting harmful free superoxide radicals to hydrogen peroxide and oxygen in the body. Extensive structural studies have established that disease-causing mutations in SOD1 reduce the ability of protein to fold, bind metal cofactors and form the disulphide bond. As a result, mutant SOD1 is prone to misfolding and aggregation. Global efforts to correct this ‘gain-of-function’ have led to identification of a variety of ‘ligand-binding pockets’ that are suitable for drug development. Ebselen, an organoselenium compound with strong antioxidant activity, has been shown to rescue SOD1 from aggregation, especially in the A4V mutant. This discovery is the starting point for guiding discovery of the next generation of compounds aimed at stabilizing SOD1 mutants.
The student will build on this success in a multidisciplinary programme using molecular biology, protein chemistry, protein crystallography and human cell line assays. Required ’wet-lab’ facilities for the project (e.g. cloning, expression and purification of proteins) are available at our institution. Additionally, UoL has a combined SAXS/MX facility on a super bright in-house X-ray generator FR-E+ and a crystallization robot.
Candidates must have, or expect to gain, a first or strong upper second class degree (or equivalent) in a relevant discipline.
Applications will be reviewed until a suitable candidate is appointed.
The successful applicant will be expected to provide the funding for tuition fees and living expenses as well as research costs of £3000 per year.
Details of costs can be found on the University website: View Website
Ligand binding and aggregation of pathogenic SOD1. Wright G.S. et al., (2013) Nature Communications 4, 1758 [DOI: 10.1038/ncomms2750].
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