Hepatitis C virus (HCV) is one of the leading causes of hepatocellular carcinoma worldwide. HCV-neutralizing antibody AP33 recognizes a linear, highly conserved epitope on the viral entry protein E2, disrupting the interaction with the cellular receptor CD81 that leads to viral entry. AP33-related anti-idiotypes (Ab₂s) have the potential to carry the internal image of the antigen E2, eliciting the production of AP33-like antibodies in humans. This study reports the mid-resolution structure of the Fab fragment of anti-idiotype A164.3 and the high-resolution structure of the Fab fragment of AP33 in complex with the Fv fragment of anti-idiotype B2.1A. Analysis of the structures and comparison with the previously published structure of AP33 in complex with a peptide corresponding to the E2 epitope, suggests that while A164.3 does not mimic the antigen E2, B2.1A is characterized by high surface complementarity with AP33 and functional antigen mimicry. Thus, B2.1A can be classified as an Ab₂-β, a subgroup of anti-idiotypes carrying the internal image of the antigen. Preliminary binding studies show that AP33 binds B2.1A with nanomolar affinity, supporting the role of B2.1A as an idiotypic vaccine candidate. Zaire ebola virus causes severe, often lethal hemorrhagic fever in humans. Ebola virus polymerase cofactor VP35 is a multifunctional protein involved in, among other functions, dsRNA binding and inhibition of the host's interferon pathways. VP35 contains an N-terminal oligomerization domain and a C-terminal dsRNA-binding domain (RBD). Preliminary results on the oligomerization domain of VP35 suggest that this region contains a coiled-coil motif, as previously reported. In order to validate a recently-discovered dsRNA end-capping pocket as a drug target, the structure of VP35 RBD I278A mutant was solved at high resolution, showing that even a small perturbation in the binding pocket can cause dramatic binding impairment due to loss of contacts with dsRNA.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:668835 |
| Date | January 2015 |
| Creators | Fadda, Valeria |
| Contributors | Taylor, Garry L. |
| Publisher | University of St Andrews |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/10023/7703 |
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