Prof Ehmke Pohl
No more applications being accepted
Funded PhD Project (UK Students Only)
About the Project
Analogues of the all-trans-retinoic acid (ATRA) play important roles in embryonic and neuronal development. Due to their key function in normal and tumor cells these compounds possess significant therapeutic potential. The biological activities of retinoids are mediated by interactions with two proteins. First of all, the molecule is bound to cellular retinoic acid-binding proteins that shuttle the water-insoluble ligand into the nucleus. Here, the molecule is transferred to a member of the retinoic acid receptors (RAR). Ligand binding causes a conformational change and enables RARs to form heterodimers regulating a wide range of genes on the transcriptional level.
Synthetic retinoids share the same chemical architecture with the natural ligand (ATRA) comprising of a hydrophobic region on one side, a variable linker and a terminal carboxylic acid function on the other side. So far, a number of synthetic analogues have been designed, synthesized and characterized. Importantly, in spite of their high chemical similarity these compounds show remarkably different binding affinities to their targets and pronounced differences in biological activities.
The aim of this project is to define the molecular basis of how synthetic retinoids elicit specific biological responses. The insight gained from structural studies combined with biophysical characterization of protein-ligand interaction and cell biological assays will be used to design new ligands. Biophysical experiments including surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) will be used to characterize the kinetics and thermodynamics of ligand binding to the proteins targets cellular). Crystal structures of protein-ligand complexes will be determined to unravel the molecular basis of binding selectivity. Protein expression and crystallization of the protein targets are well established in the group. Based on the results obtained new synthetic retinoids will be synthesized and tested in biophysical and cell biological assays.
Applicants should contact Dr Ehmke Pohl ([Email Address Removed]) with a covering letter, cv and the names of two suitable referees. Potential applicants are also welcome to contact Dr Pohl with informal enquiries.
Early applications are strongly encouraged. The position will be filled when a suitable candidate is identified.
Closing date: 31 July 2016.
Funding Notes
Fully funded 4-year MRC CASE studentship. The position is only open to applicants who are resident in the UK for fee purposes.
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