4.5 Article

Structural insights into the binding of hepatitis B virus core peptide to HLA-A2 alleles: Towards designing better vaccines

Journal

EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 41, Issue 7, Pages 2097-2106

Publisher

WILEY-BLACKWELL
DOI: 10.1002/eji.201041370

Keywords

Antigen; Hepatitis B virus; Human leukocyte antigen; Immunogenicity; Vaccine

Categories

Funding

  1. Agency for Science, Technology and Research (A*STAR)

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Binding of specific antigenic peptides with human leukocyte antigen (HLA) molecules is a prerequisite for the initiation of T-cell responses and structural information about the peptide-HLA complex is essential for the detailed understanding of such interactions. HLA-A2 is the most prevalent HLA allele globally but aside from A*02:01 there is a significant lack of crystal structures, particularly for alleles that occur in high frequencies among Asian populations. Here, we report three HLA-A2 structures with the immunodominant hepatitis B core antigen 18-27 (HBcAg18-27) epitope, namely A*02:03, A*02:06, and A*02:07 at resolutions of 2.16, 1.70, and 1.75 angstrom respectively. This comparative analysis reveals that minor polymorphic residue changes between different HLA alleles can induce significant alterations in the major histocompatibility complex-peptide interface, and introduce conformational changes in the p3-p8 peptide region. Circular dichroism analysis demonstrated the HLA-A2-peptide complexes to have a hierarchy of thermostability and binding affinity in the order of A*02:06>A*02:07>A*02:01>A*02:03. Our findings provide structural insights into the varied HLA-A2 allele binding of the hepatitis B core antigen 18-27 epitope and the data suggest that chemical modifications of the peptide side chains could be a promising strategy to modulate and improve HLA-A2-peptide binding affinity for vaccine design.

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