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|Title:||Structural basis for the neutralization and genotype specificity of hepatitis E virus||Authors:||Tang, X.
|Issue Date:||21-Jun-2011||Citation:||Tang, X., Yang, C., Gu, Y., Song, C., Zhang, X., Wang, Y., Zhang, J., Hew, C.L., Li, S., Xia, N., Sivaraman, J. (2011-06-21). Structural basis for the neutralization and genotype specificity of hepatitis E virus. Proceedings of the National Academy of Sciences of the United States of America 108 (25) : 10266-10271. ScholarBank@NUS Repository. https://doi.org/10.1073/pnas.1101309108||Abstract:||Hepatitis E virus (HEV) causes acute hepatitis in humans, predominantly by contamination of food and water, and is characterized by jaundice and flu-like aches and pains. To date, no vaccines are commercially available to prevent the disease caused by HEV. Previously,we showed that amonoclonal antibody, 8C11, specifically recognizes a neutralizing conformational epitope onHEV genotype I. The antibody 8C11 blocks the virus-like particle from binding to and penetrating the host cell. Here, we report the complex crystal structure of 8C11 Fab with HEV E2s(I) domain at 1.9 Å resolution. The 8C11 epitopes on E2s(I) were identified at Asp 496-Thr 499, Val 510-Leu 514, and Asn 573-Arg 578. Mutations and cell-model assays identified Arg 512 as the most crucial residue for 8C11 interaction with and neutralization of HEV. Interestingly, 8C11 specifically neutralizes HEV genotype I, but not the other genotypes. Because HEV type I and IV are the most abundant genotypes, to understand this specificity further we determined the structure of E2s(IV) at 1.79 Å resolution and an E2s(IV) complex with 8C11 model was generated. The comparison between the 8C11 complexeswith type I and IV revealed the key residues that distinguish these two genotypes. Of particular interest, the residue at amino acid position 497 at the 8C11 epitope region of E2s is distinct among these two genotypes. Swapping this residue from one genotype to another inversed the 8C11 reactivity, demonstrating the essential role played by amino acid 497 in the genotype recognition. These studies may lead to the development of antibody-based drugs for the specific treatment against HEV.||Source Title:||Proceedings of the National Academy of Sciences of the United States of America||URI:||http://scholarbank.nus.edu.sg/handle/10635/115300||ISSN:||00278424||DOI:||10.1073/pnas.1101309108|
|Appears in Collections:||Staff Publications|
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