title: A view of the E2-CD81 interface at the binding site of a neutralizing antibody against hepatitis C virus.
abstract: Hepatitis C virus (HCV) glycoprotein E2 is considered a major target for generating neutralizing antibodies against HCV, primarily due to its role of engaging host entry factors, such as CD81, a key cell surface protein associated with HCV entry. Based on a series of biochemical analyses in combination with molecular docking, we present a description of a potential binding interface formed between the E2 protein and CD81. The virus side of this interface includes a hydrophobic helix motif comprised of residues W(437)LAGLF(442), which encompasses the binding site of a neutralizing monoclonal antibody, mAb41. The helical conformation of this motif provides a structural framework for the positioning of residues F442 and Y443, serving as contact points for the interaction with CD81. The cell side of this interface likewise involves a surface-exposed hydrophobic helix, namely, the D-helix of CD81, which coincides with the binding site of 1D6, a monoclonal anti-CD81 antibody known to block HCV entry. Our illustration of this virus-host interface suggests an important role played by the W(437)LAGLF(442) helix of the E2 protein in the hydrophobic interaction with the D-helix of CD81, thereby facilitating our understanding of the mechanism for antibody-mediated neutralization of HCV.
  
  
  OBJECTIVE
  Characterization of the interface established between a virus and host cells can provide important information that may be used for the control of virus infections. The interface that enables hepatitis C virus (HCV) to infect human liver cells has not been well understood because of the number of cell surface proteins, factors, and conditions found to be associated with the infection process. Based on a series of biochemical analyses in combination with molecular docking, we present such an interface, consisting of two hydrophobic helical structures, from the HCV E2 surface glycoprotein and the CD81 protein, a major host cell receptor recognized by all HCV strains. Our study reveals the critical role played by hydrophobic interactions in the formation of this virus-host interface, thereby contributing to our understanding of the mechanism for antibody-mediated neutralization of HCV.
authors.affiliation: Division of Hematology Research and Review, Office of Blood Research and Review, Center for Biologics Evaluation and Research, FDA, Silver Spring, Maryland, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Harman
authors.affiliation: Division of Hematology Research and Review, Office of Blood Research and Review, Center for Biologics Evaluation and Research, FDA, Silver Spring, Maryland, USA.
authors.forename: Lilin
authors.initials: L
authors.lastname: Zhong
authors.affiliation: Division of Hematology Research and Review, Office of Blood Research and Review, Center for Biologics Evaluation and Research, FDA, Silver Spring, Maryland, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.affiliation: Division of Hematology Research and Review, Office of Blood Research and Review, Center for Biologics Evaluation and Research, FDA, Silver Spring, Maryland, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Liu
authors.affiliation: Division of Hematology Research and Review, Office of Blood Research and Review, Center for Biologics Evaluation and Research, FDA, Silver Spring, Maryland, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Deng
authors.affiliation: Division of Hematology Research and Review, Office of Blood Research and Review, Center for Biologics Evaluation and Research, FDA, Silver Spring, Maryland, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Division of Hematology Research and Review, Office of Blood Research and Review, Center for Biologics Evaluation and Research, FDA, Silver Spring, Maryland, USA.
authors.forename: Hailing
authors.initials: H
authors.lastname: Yan
authors.affiliation: Division of Hematology Research and Review, Office of Blood Research and Review, Center for Biologics Evaluation and Research, FDA, Silver Spring, Maryland, USA.
authors.forename: Evi
authors.initials: E
authors.lastname: Struble
authors.affiliation: Division of Hematology Research and Review, Office of Blood Research and Review, Center for Biologics Evaluation and Research, FDA, Silver Spring, Maryland, USA.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Virata-Theimer
authors.affiliation: Division of Hematology Research and Review, Office of Blood Research and Review, Center for Biologics Evaluation and Research, FDA, Silver Spring, Maryland, USA pei.zhang@fda.hhs.gov.
authors.forename: Pei
authors.initials: P
authors.lastname: Zhang
mesh_terms: D057134:Antibodies, Neutralizing / Q000378:metabolism; D000914:Antibodies, Viral / Q000378:metabolism; D001665:Binding Sites; D016174:Hepacivirus / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D011991:Receptors, Virus / Q000737:chemistry / Q000378:metabolism; D060225:Tetraspanin 28 / Q000737:chemistry* / Q000378:metabolism*; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000378:metabolism*; D053585:Virus Attachment
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; C554798:CD81 protein, human; D011991:Receptors, Virus; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus