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Title page for ETD etd-04292013-210116


Type of Document Dissertation
Author Aiyegbo, Mohammed Sefiu
Author's Email Address m.aiyegbo@gmail.com
URN etd-04292013-210116
Title Structural analysis of rotavirus antigen – antibody interactions
Degree PhD
Department Microbiology and Immunology
Advisory Committee
Advisor Name Title
James W. Thomas Committee Chair
Benjamin Spiller Committee Member
James E. Crowe, Jr. Committee Member
Phoebe Stewart Committee Member
Terence Dermody Committee Member
Keywords
  • X-ray crystallography
  • DXMS
  • Transcription inhibition
  • quasi-equivalence
  • vaccine
  • Structure
  • Cryo-EM
Date of Defense 2013-02-12
Availability unrestricted
Abstract
Previous human antibody studies have shown that the human VH1-46 antibody variable gene encodes much of the naturally-occurring human B cell response to rotavirus, and is directed to virus protein 6 (VP6). It is currently unknown why some of the VH1-46 encoded human VP6 monoclonal antibodies inhibit viral transcription while others do not. Here, I used a hybrid methods approach for antibody epitope mapping including x-ray crystallography, single particle cryo-electron microscopy (cryo-EM), enhanced amide hydrogen/deuterium exchange mass spectroscopy (DXMS) and computational modeling to determine the location and mode of binding of an inhibitory (RV6-26) and non-inhibitory (RV6-25) VH1-46 antibody. These studies showed that the location of binding of the non-inhibitory antibody RV6-25 on the apical surface of RV VP6 head domain does not obstruct the transcription pore upon antibody binding, in contrast to binding of the inhibitory antibody RV6-26 deeper in the transcriptional pore to sterically block the pore and hence inhibit transcription. In addition, these studies reveal intricate binding patterns of both antibodies to VP6 that inform on the structural arrangement of VP6 molecules in the virion particle.

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