About the Project
The information encoded in the human genome is translated in the form of proteins that function by interacting with a variety of targets. “High affinity” protein-ligand interactions have been extensively investigated, as they are amenable to a number of analytical techniques. However, for “weak” protein interactions many conventional approaches fail or become unreliable. Significantly, our growing understanding of the dynamics and complexity of biological systems ("systems biology") has revealed many examples where weak protein interactions play crucial roles, when quick cellular responses are required after temporary stimuli (signal transduction, reversible cell-cell contacts, transient interactions in host/pathogen recognition, leucocyte rolling, etc.). For a complete understanding of life processes, it is necessary to investigate both strong and weak protein-ligand interactions. There is a clear need for novel accurate approaches to be able to characterize the 3D structure of weak protein complexes.
Among the NMR techniques for weak interactions, saturation transfer difference (STD) NMR has become one of the most powerful and versatile, with applications both in academic research as well as in pharma industry (drug discovery). This PhD project will involve the development of novel STD NMR implementations and protocols to pave the way for “fast” quantitative STD NMR studies. Protein-glycan systems of biological interest will be the subject of study. The project is offered to an enthusiastic candidate with a first class or 2.1 degree in Physics, Chemistry, Biology, or Pharmacy. The selected candidate will work in well-equipped laboratories, with access to state of the art High Performance Computing Cluster (302 node cluster providing a total of 4148 cores) and powerful NMR equipment (800 MHz, 2x 500 MHz, 2x 400 MHz, and 300 MHz spectrometers, equipped with different liquid-, solid-state, and HR-MAS probe heads), in a highly stimulating scientific environment that includes collaboration with internationally distinguished scientists at UEA and the wider Norwich Research Park (NRP).
For more information on the supervisor for this project, please go here: https://www.uea.ac.uk/pharmacy/people/profile/j-angulo
Type of programme: PhD
Start date of project: October 2018
Mode of study: Full time
Funding Notes
This PhD project is offered on a self-funding basis. It is open to applicants with funding or those applying to funding sources. Details of tuition fees can be found at http://www.uea.ac.uk/study/postgraduate/research-degrees/fees-and-funding.
A bench fee is also payable on top of the tuition fee to cover specialist equipment or laboratory costs required for the research. The amount charged annually will vary considerably depending on the nature of the project and applicants should contact the primary supervisor for further information about the fee associated with the project.
Acceptable first degree: Chemistry, Pharmacy, Biology, Physics
The standard minimum entry requirement is 2:1.
References
i) Angulo, J., Goffin S. A., Gandhi D., Searcey M., Howell L.A. Unveiling the “Three-Finger Pharmacophore” Required for p53-MDM2 Inhibition by Saturation Transfer Difference (STD) NMR Initial Growth Rates Approach. Chem. Eur. J. 2016, 22, 5858-5862.
ii) Munoz-Garcia, J. C.; Chabrol, E.; Vives, R. R.; Thomas, A.; de Paz, J. L.; Rojo, J.; Imberty, A.; Fieschi, F.; Nieto, P. M.; Angulo, J., Langerin-Heparin Interaction: Two Binding Sites for Small and Large Ligands As Revealed by a Combination of NMR Spectroscopy and Cross-Linking Mapping Experiments. J Am Chem Soc 2015, 137 (12), 4100-4110.
iii) Angulo, J.; Nieto, P., STD-NMR: application to transient interactions between biomolecules—a quantitative approach. Eur Biophys J 2011, 40 (12), 1357-1369.
iv) Angulo, J.; Enriquez-Navas, P. M.; Nieto, P. M., Ligand-Receptor Binding Affinities from Saturation Transfer Difference (STD) NMR Spectroscopy: The Binding Isotherm of STD Initial Growth Rates. Chem. Eur. J. 2010, 16 (26), 7803-7812.
v) Angulo, J.; Rademacher, C.; Biet, T.; Benie, A. J.; Blume, A.; Peters, H.; Palcic, M.; Parra, F.; Peters, T., NMR Analysis of Carbohydrate–Protein Interactions. Methods in Enzymology, Minoru, F., Ed. Academic Press: 2006; Vol. Volume 416, pp 12-30.
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