Heparan Sulphate plays an important role in many life processes and so an understanding of its role as a universal co-receptor is of great importance. Traditionally oligosaccharides derived from the related molecule heparin have been at the forefront of molecular drug design, due to its similarity in structure and function. To obtain a more complex and detailed picture of the role of HS in structural biology further complex work must be undertaken on HS. Here in this study a number of HS derived octasaccharides have been purified. Alongside this is work carried on HS derived decasaccharides, of which all have undergone extensive molecular modelling simulations. The role of the Iduronates in the HS structure, at monosaccharide level has indicated a major role for these structures in biological activity. Further work has indicated the level of sulphation is also a requirement which in turn influences conformational behaviour. Up until now this has only really been studied at the monosaccharide level and so this study has generated a number of different HS models which can confirm the importance of iduronate conformation in biological activity. Not only that but it has also been identified that certain torsional geometries within the glycosidic bonds between monosaccharides also has a major influence on conformation. Local deviations in the molecular modelling data suggest there is a slight difference between active and inactive oligosaccharides with the ability to bind and activate the HS:FGF2:FGFR IIIc complex. The implications of these and other structural insights are discussed with the implication heavily towards a combination of both torsional geometry and iduronate conformation in biological activity. To further aid our understanding HS dp10 oligosaccharides were docked into a FGF2 which was in a complex with a heparin hexasaccharide. Docking experiments were carried in order to attain structural information on the binding of these molecules. The Goodger oligosaccharides were docked into the X-ray crystal structure and were chosen specifically for their iduronate conformation or the torsional geometry.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:535324 |
| Date | January 2011 |
| Creators | Swift, Simone |
| Contributors | Cooke, David ; Pye, David ; Murphy, Kevin |
| Publisher | University of Huddersfield |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://eprints.hud.ac.uk/id/eprint/10739/ |
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