title: Structural insights into the binding of hepatitis B virus core peptide to HLA-A2 alleles: towards designing better vaccines.
abstract: 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 Å 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.
authors.affiliation: Singapore Immunology Network, A*STAR, Immunos, Singapore.
authors.forename: Jingxian
authors.initials: J
authors.lastname: Liu
authors.forename: Kenneth Y
authors.initials: KY
authors.lastname: Chen
authors.forename: Ee C
authors.initials: EC
authors.lastname: Ren
mesh_terms: D000483:Alleles; D002460:Cell Line; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D015789:HLA-A2 Antigen / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006512:Hepatitis B Core Antigens / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D017325:Hepatitis B Vaccines; D006515:Hepatitis B virus / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D015789:HLA-A2 Antigen; D006512:Hepatitis B Core Antigens; D017325:Hepatitis B Vaccines; D016056:Immunodominant Epitopes