| EPSRC Reference: |
EP/F043481/1 |
| Title: |
Determining three-dimensional structures of challenging biosolids: Advancing solid-state NMR methodology |
| Principal Investigator: |
Becker-Baldus, Ms J |
| Other Investigators: |
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| Department: |
Physics |
| Organisation: |
University of Warwick |
| Scheme: |
Postdoc Research Fellowship |
| Starts: |
01 September 2008 |
Ends: |
28 February 2010 |
Value (£): |
260,257
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| EPSRC Research Topic Classifications: |
| Analytical Science |
Cells |
| Chemical Biology |
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| EPSRC Industrial Sector Classifications: |
| No relevance to Underpinning Sectors |
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Summary on Grant Application Form |
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Nearly all body functions are controlled by proteins, including the function of senses and the immune system, but also the formation of cancer and other diseases. Thus they play a crucial role in disease development and cure. When aiming to find new treatments for maladies it is necessary to understand the underlying causes and thus the role of the corresponding proteins. Proteins are long molecular chains and their function is determined by their three dimensional arrangement, which is also referred to as fold. Therefore the knowledge of this fold is crucial in understanding protein function and disease. It also provides precious information for the developers of new drugs, which specially design molecules that interact with the proteins involved in a specific disease. The field of Structural Biology therefore aims to determine the fold of proteins. This requires the use of techniques which can elucidate structure on an atomic level. So far most protein structures have been determined using X-ray crystallography and solution state nuclear magnetic resonance (NMR). However a large group of proteins is very difficult to study with these techniques. They include membrane proteins (proteins that are embedded into the wall of cells and cellular compartments), controlling cellular functions, and amyloid deposits, found in many neuro degenerative diseases such as Alzheimer's and Parkinson's and prion diseases. Thus a very important class of proteins cannot be tackled with the established techniques. However, during the last decade solid state NMR has developed quickly and is starting to become a tool to fill this gap. A way to determine protein structure is to measure distances between single atoms of the biopolymer. This can be done using solid state NMR. However it is still a challenge to determine a large enough number of such distances in a large protein molecules. This is not only due to the complex appearance of the spectra resulting from such large molecules, but also because in the presence of several NMR active nuclei (the inner part of the atoms), which are introduced to make the whole molecule visible in NMR experiments, many solid state NMR techniques are inefficient or only yield inaccurate distances. Thus method development is mandatory to make this technique an efficient tool for structure determination of membrane proteins and amyloid fibrils.NMR spectroscopy relies on the presence of a magnetic field, which result in an orientation of the magnetic moments, present in NMR active nuclei. This makes an interaction of the sample with irradiated radio waves possible which can be used to record spectra. The resolution in this spectra is improved by the usage of very high magnetic fields which are increasingly used in structural biology. However, some experiments work most efficient at moderate magnetic fields. Therefore the performance of these experiments have to be evaluated for high magnetic fields and new methods have to be developed.Another way to obtain more information that can be used for structure determination, is the usage of so far rarely used nuclei. Hydrogen bonds between oxygen and nitrogen are very important structural features of bio-molecules, but have so far not been investigated due to difficulties when working with the oxygen nucleus. Most oxygen atoms are not NMR active, and the intrinsic properties of the only NMR active type (isotope) of oxygen (17O) make its use awkward. However, progress in the introduction of 17O into bio-molecules and solid state NMR methods for this nucleus make its use attractive.In summary, the research into the method development of solid state NMR techniques for the application to bio-molecules will help to efficiently use solid state NMR for the investigation of proteins which are otherwise difficult to study and are of great importance in the understanding of diseases and the development of therapeutics.
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Key Findings |
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This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
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Potential use in non-academic contexts |
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This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
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Impacts |
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| Description |
This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk |
| Summary |
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| Date Materialised |
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Sectors submitted by the Researcher |
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This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
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| Project URL: |
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| Further Information: |
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| Organisation Website: |
http://www.warwick.ac.uk |