On the basis of preliminary infonnation from genome projects it has been estimated that approximately 10000 different membrane proteins could exist in the human being. A membrane protein of some description is involved in nearly every biochemical pathway, therefore knowledge of their structure is essential for detennination of function and for rational drug design. Membrane proteins are extremely hard to crystallize due to their amphipathic nature and therefore we explore other structural detennination methods in order to gain infonnation about membrane proteins. These methods are, membrane protein sequence analysis, molecular modeling, conventional circular dichroism (CD) and synchrotron radiation circular dichroism spectroscopy (SRCD) which enable a detennination of structure, function and can be used as a basis for rational drug design. Sequence analysis studies were undertaken on the defective gene product of CLN2 which is involved in the neurodegenerative disease late infantile neuronal ceroid lipofuscinoses (LINCL). A one transmembrane helix structure is proposed for this membrane protein. A model is proposed for its structure in membranes, and how it may function as a proteinase to aid in the maturation of subunit c of the mitochondrial A TP complex. Its role is contrasted with that of the CLN3 protein, which is involved in the juvenile form of the disease. Molecular modeling studies were undertaken on the endothelin G-protein coupled receptor. The endothelins are important regulators of the vascular system and endothelin-l is the most potent vasoconstrictor yet characterized. Computational docking studies have been undertaken in order to detennine whether endothelins that have been isolated bind to the modeled receptor. The model of the receptor/ligand complexes produced forms a basis for rational drug design of agonists and antagonists for this G-protein coupled receptor. Conventional circular dichroism spectroscopy has been used to analyze the effects of organic solvents on the membrane protein bacteriorhodopsin. Circular dichroism analysis was also undertaken on membrane proteins whose crystal 2 structures have already been detennined. These studies involved using SRCD which enables low wavelength data to be obtained. Inclusion of data in this wavelength region in reference databases used for calculations of secondary structures could provide for much better accuracy in determination of the content of sheet, tum, polyproline II and aperiodic types of secondary structures.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:248128 |
| Date | January 2001 |
| Creators | Orry, Andrew John Wooldridge |
| Publisher | Birkbeck (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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