title: Structural evidence for a bifurcated mode of action in the antibody-mediated neutralization of hepatitis C virus.
abstract: Hepatitis C virus (HCV) envelope glycoprotein E2 has been considered as a major target for vaccine design. Epitope II, mapped between residues 427-446 within the E2 protein, elicits antibodies that are either neutralizing or nonneutralizing. The fundamental mechanism of antibody-mediated neutralization at epitope II remains to be defined at the atomic level. Here we report the crystal structure of the epitope II peptide in complex with a monoclonal antibody (mAb#8) capable of neutralizing HCV. The complex structure revealed that this neutralizing antibody engages epitope II via interactions with both the C-terminal α-helix and the N-terminal loop using a bifurcated mode of action. Our structural insights into the key determinants for the antibody-mediated neutralization may contribute to the immune prophylaxis of HCV infection and the development of an effective HCV vaccine.
authors.affiliation: Division of Hematology, Office of Blood Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Deng
authors.forename: Lilin
authors.initials: L
authors.lastname: Zhong
authors.forename: Evi
authors.initials: E
authors.lastname: Struble
authors.forename: Hongying
authors.initials: H
authors.lastname: Duan
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.forename: Christine
authors.initials: C
authors.lastname: Harman
authors.forename: Hailing
authors.initials: H
authors.lastname: Yan
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Virata
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zhao
authors.forename: Stephen
authors.initials: S
authors.lastname: Feinstone
authors.forename: Harvey
authors.initials: H
authors.lastname: Alter
authors.forename: Pei
authors.initials: P
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000737:chemistry* / Q000276:immunology*; D018360:Crystallography, X-Ray; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D016174:Hepacivirus / Q000276:immunology*; D018937:Hepatitis C Antibodies / Q000737:chemistry* / Q000276:immunology*; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry; D009500:Neutralization Tests; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D017433:Protein Structure, Secondary; D055672:Static Electricity
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000939:Epitopes; D018937:Hepatitis C Antibodies; D050505:Mutant Proteins; D010455:Peptides