Broadly neutralizing anti-hepatitis B virus antibody reveals a complementarity determining region H3 lid-opening mechanism.
The humanized monoclonal antibody HzKR127 recognizes the preS1 domain of the human hepatitis B virus surface proteins with a broadly neutralizing activity in vivo. We present the crystal structures of HzKR127 Fab and its complex with a major epitope peptide. In the complex structure, the bound peptide forms a type IV beta-turn followed by 3(10) helical turn, the looped-out conformation of which provides a structural basis for broad neutralization. Upon peptide binding, the antibody undergoes a dramatic complementarity determining region H3 lid opening. To understand the structural implication of the virus neutralization, we carried out comprehensive alanine-scanning mutagenesis of all complementarity determining region residues in HzKR127 Fab. The functional mapping of the antigen-combining site demonstrates the specific roles of major binding determinants in antigen binding, contributing to the rational design for maximal humanization and affinity maturation of the antibody.
Chi
Seung-Wook
SW
Center for Cellular Switch Protein Structure, Molecular Cancer Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Korea.
Maeng
Cheol-Young
CY
Kim
Seung Jun
SJ
Oh
Mee Sook
MS
Ryu
Chun Jeih
CJ
Kim
Sang Jick
SJ
Han
Kyou-Hoon
KH
Hong
Hyo Jeong
HJ
Ryu
Seong Eon
SE
D000595:Amino Acid Sequence; D000941:Antigens / Q000737:chemistry / Q000276:immunology; D001665:Binding Sites; D022801:Complementarity Determining Regions / Q000737:chemistry* / Q000276:immunology* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D006510:Hepatitis B Antibodies / Q000737:chemistry* / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000737:chemistry; D020836:Protein Structure, Quaternary; D012680:Sensitivity and Specificity; D014764:Viral Proteins / Q000737:chemistry / Q000276:immunology
D000941:Antigens; D022801:Complementarity Determining Regions; D006510:Hepatitis B Antibodies; D010455:Peptides; D014764:Viral Proteins