Structure guided inhibitors design of human Mitochondrial Thymidine Kinase (TK2)
Dr Y Jin
Friday, March 15, 2019
Mitochondrial Thymidine Kinase 2 (TK2) catalyses transfer of a γ-phosphate group from ATP to the 5′-hydroxyl group of thymidine, deoxycytidine, or deoxyuridine to form their 5’-mono-phosphates. Deficiency in TK2 activity due to genetic mutation causes devastating mitochondrial DNA depletion syndrome (MDS), affecting mainly liver and skeletal muscle. Per contra, active TK2 in human tumour cells can reduce effectiveness of the anti-cancer drug gemcitabine by phosphorylating deoxycytidine which eventually leads to the generation of dCTP. TK2 is thus proven to be a drug target for development of both activators and inhibitors.
Despite the importance of TK2, there is a fundamental lack of structural information about TK2, which is a real barrier to a clear understanding of its biological function and targeted drug design.
Aims and methods
We will use a powerful set of chembiological techniques, namely NMR and x-ray crystallography, in combination with the utilisation of inorganic and synthetic bisubstrate analogues to perform functional and structural characterization of TK2, and thereby significantly advance knowledge of this drugable mitochondrial enzyme.
The project will offer the candidate the necessary and comprehensive training in molecular biology, biochemistry, structural biology, and drug discovery within 3.5 years. It is particular suitable for candidate who has strong synthetic chemistry background wanting to move into the field of drug discovery.
Applicants with at least a Second Class degree in Chemistry, Pharmaceutical Sciences, Biochemistry, or related disciplines will be considered if they also have a master’s degree. Candidates with strong maths and physics at UK A levels are particularly favourable. Applicants with a minimum Upper Second Class degree and significant relevant non-academic experience are also encouraged to apply.
Papers to read: Current Pharmaceutical Design, 2012, 18, 2981-2994
Supervisor: Dr Yi Jin https://www.cardiff.ac.uk/people/view/742977-jin-yi
Start date: 1 April 2019
Tuition fee support - Full UK/EU tuition fees
Maintenance stipend - Doctoral stipend matching UK Research Council National Minimum
Additional funding offered
Additional funding is available over the course of the programme and will cover costs such as research consumables, training, conferences and travel.
Residency - UK Research Council eligibility conditions apply. For more details view our website https://www.cardiff.ac.uk/study/postgraduate/funding/view/epsrc-doctoral-training-partnership-phd-in-chemistry
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