Structure-function studies of viral RNA-dependent RNA polymerases

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dc.contributor.advisorNg, Kenneth Kai Sing
dc.contributor.authorSamanta, Soumya
dc.contributor.committeememberZimmerly, Steven
dc.contributor.committeememberNoskov, Sergei Yu
dc.contributor.committeememberWilliams, Gareth J.
dc.contributor.committeememberGlover, Mark
dc.date2019-06
dc.date.accessioned2018-09-27T18:06:57Z
dc.date.available2018-09-27T18:06:57Z
dc.date.issued2018-09-18
dc.description.abstractHuman norovirus (NV) and hepatitis C virus (HCV) are two major and related human pathogens belonging to the positive-strand RNA virus superfamily. NV belongs in the Caliciviridae family and is a major cause of gastroenteritis outbreaks throughout the world. Although there is substantial interest in the development of vaccines and antiviral therapeutics for norovirus infections, there are currently no effective antiviral treatments. Using a fluorescence-based primer extension assay, I have identified a series of structurally-related compounds that inhibit norovirus polymerase at micromolar concentrations. Previous work in our group has helped to structurally characterize human norovirus polymerase complexes with RNA, nucleoside triphosphates, and divalent metal ions. These structures have revealed the enzyme trapped indifferent conformations that are likely important for the catalytic cycle. Several enzyme-inhibitor complexes with alendronic acid and medronic acid inhibitors have been crystallized, and the structure determination of NV Pol complexes has been undertaken. This thesis presents new results correlating enzyme inhibition kinetics with crystallographic structure determination for several novel inhibitor complexes. In the second part of this thesis, work is described on characterizing interactions between RNA and HCV non-structural protein NS5B, the RNA-dependent RNA Polymerase (RDRP) central to HCV replication. HCV NS5B is highly-conserved and forms the core of the catalytic site of the replicase complex. I have determined the structure of a novel polymerase-RNA complex that shows the binding of a short RNA oligonucleotide to a region of the enzyme near a commonly-targeted site for the binding of allosteric inhibitors.en_US
dc.identifier.citationSamanta, S. (2018). Structure-function studies of viral RNA-dependent RNA polymerases (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/33047en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/33047
dc.identifier.urihttp://hdl.handle.net/1880/108694
dc.language.isoeng
dc.publisher.facultyGraduate Studies
dc.publisher.facultyScience
dc.publisher.institutionUniversity of Calgaryen
dc.publisher.placeCalgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subjectMacromolecular crystallography
dc.subjectProtein purification
dc.subjectPolymerase
dc.subjectHepatitis C
dc.subjectNorovirus
dc.subject.classificationVirologyen_US
dc.subject.classificationBiophysicsen_US
dc.subject.classificationBiochemistryen_US
dc.titleStructure-function studies of viral RNA-dependent RNA polymerases
dc.typedoctoral thesis
thesis.degree.disciplineBiological Sciences
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameDoctor of Philosophy (PhD)
ucalgary.item.requestcopytrue
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