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Unravelling the mysteries of retinoid signalling -EPSRC Centre for Doctoral Training (CDT) in Molecular Sciences for Medicine (MoSMed)

  • Full or part time
  • Application Deadline
    Friday, March 06, 2020
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Retinoid acid (RA) and its natural and synthetic derivatives control a wide range of cellular processes in chordates, including differentiation, proliferation, apoptosis and homeostasis, by regulating transcriptional control in the cell nucleus. Retinoids are high affinity ligands for a family of nuclear receptor proteins - retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Once bound to these receptors, dimerization allows the formation heterodimers that are able to bind their target DNA sequences. To reach the nucleus, the highly lipophilic retinoids are bound to a carrier protein, the Cellular Retinoic Acid Binding Protein (CRABPII). The overall goal of this project is to develop an entire tool box of synthetic specific retinoids that are specific for application ranging from drug discovery to fluorescent probes in cell biology.
Work Package 1: Biophysical and biochemical characterization
In this WP the student will characterize the specificity of binding of all compounds to CRABPII and the three RAR isoforms.. The interactions of CRAPBII with the ligand binding domains of all RARs as well as with Cyclin D will be investigated using the FRET assays developed in the group of Prof. J. Endicott (NCRI, NCL).
WP 2: Structural Characterisation
In order to unravel the molecular basis of compounds that exhibit specific binding properties or elicit unexpected biological activities the student will determine the X-ray co-crystal structures of selected compounds with their target proteins. While it is expected that all biologically active compounds bind CRAPBII, the binding pockets of the three RAR proteins differ significantly. High-resolution crystal structures will inform future design of novel compounds and serve as a starting point for high-level molecular dynamics simulations.
Exploring protein-protein interactions
In order to investigate the mechanisms by which retinoids elicit the specific biological response the student will utilize those compounds that stabilize CRABPII-RAR complexes for further biophysical and cell biological and biophysical characterization. straightforward FRET assays could lead to structural characterization by either MX or cryCryoEM.

Funding Notes

The award is available to UK/EU applicants only. Depending on how you meet the EPSRC’s eligibility criteria, you may be entitled to a full or a partial award.

References

Applicants should hold or expect to achieve an excellent Masters level degree in structural chemistry or biochemistry. An excellent Bachelors degree with relevant experience will also be considered.

For more information regarding MoSMed please visit the webpage: https://research.ncl.ac.uk/mosmed. Please note that MoSMed is a joint venture between Durham and Newcastle Universities.

When making an application, please select the course code F1A201 and quote the project title and reference number MoSMed20-09.

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