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dc.contributor.advisorGeorge, Graham N.en_US
dc.creatorZhang, Limeien_US
dc.date.accessioned2009-06-04T07:52:16Zen_US
dc.date.accessioned2013-01-04T04:34:45Z
dc.date.available2010-06-09T08:00:00Zen_US
dc.date.available2013-01-04T04:34:45Z
dc.date.created2009en_US
dc.date.issued2009en_US
dc.date.submitted2009en_US
dc.identifier.urihttp://hdl.handle.net/10388/etd-06042009-075216en_US
dc.description.abstractX-ray absorption spectroscopy and computational chemistry have been used to probe the structure of biomolecules involved in cellular copper homeostasis. X-ray absorption spectroscopy shows that copper chaperones involved in cytochrome c oxidase assembly bind Cu(I) with trigonal coordination environments in poly-copper thiolate clusters, but the number of coppers in these clusters remains unclear. X-ray absorption spectroscopy of the metal-sensing transcription factor-1 from Drosophila melanogaster and metallothionein from Saccharomyces cerevisiae with stoichiometries of four or less shows a tetracopper cluster in an all-or-none manner in these molecules. These results suggest that cooperative binding of copper to form tetracopper clusters may be a common mechanism employed by copper control molecules. The active site structure of the novel copper-sensitive repressor CsoR in Mycobacterium tuberculosis binds copper in a trigonal coordination geometry with two sulfur and one nitrogen donors according to X-ray absorption spectroscopy results. Molecular dynamics simulations of both apo- and Cu-bound CsoR reveal local conformational changes in CsoR upon copper binding, which suggests multiple possible mechanisms of Cu-dependent transcriptional regulation by CsoR. Finally, X-ray absorption spectroscopy and X-ray fluorescence imaging have been used to understand the molecular basis of a promisng new treatment for Wilson’s disease (a genetic disorder of Cu homeostasis) using tetrathiomolybdate. Overall, the results presented provide an essential structural basis for understanding copper homeostasis in living cells.en_US
dc.language.isoen_USen_US
dc.subjectdensity functional theoryen_US
dc.subjectX-ray absorption spectroscopyen_US
dc.subjectcellular Cu controlen_US
dc.subjectmolecular dynamicsen_US
dc.subjectmetallothioneinen_US
dc.subjectCu chapteroneen_US
dc.subjectCsoRen_US
dc.subjectMTF-1en_US
dc.titleStructure-function relationships in cellular copper controlen_US
thesis.degree.departmentGeological Sciencesen_US
thesis.degree.disciplineGeological Sciencesen_US
thesis.degree.grantorUniversity of Saskatchewanen_US
thesis.degree.levelDoctoralen_US
thesis.degree.nameDoctor of Philosophy (Ph.D.)en_US
dc.type.materialtexten_US
dc.type.genreThesisen_US
dc.contributor.committeeMemberNichol, Helenen_US
dc.contributor.committeeMemberEllis, Thomasen_US
dc.contributor.committeeMemberBlackburn, Ninian J.en_US
dc.contributor.committeeMemberPickering, Ingrid J.en_US


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