The E2 envelope glycoprotein is the primary target of human neutralizing antibody response against hepatitis C virus (HCV), and is thus a major focus of vaccine and immunotherapeutics efforts. There is emerging evidence that E2 is a highly complex, dynamic protein with residues across the protein that are modulating antibody recognition, local and global E2 stability, and viral escape. To comprehensively map these determinants, we performed global E2 alanine scanning with a panel of 16 human monoclonal antibodies (hmAbs), resulting in an unprecedented dataset of the effects of individual alanine substitutions across the E2 protein (355 positions) on antibody recognition. Analysis of shared energetic effects across the antibody panel identified networks of E2 residues involved in antibody recognition and local and global E2 stability, as well as predicted contacts between residues across the entire E2 protein. Further analysis of antibody binding hotspot residues defined groups of residues essential for E2 conformation and recognition for all 14 conformationally dependent E2 antibodies and subsets thereof, as well as residues that enhance antibody recognition when mutated to alanine, providing a potential route to engineer E2 vaccine immunogens. By incorporating E2 sequence variability, we found a number of E2 polymorphic sites that are responsible for loss of neutralizing antibody binding. These data and analyses provide fundamental insights into antibody recognition of E2, highlighting the dynamic and complex nature of this viral envelope glycoprotein, and can serve as a reference for development and rational design of E2-targeting vaccines and immunotherapeutics.
ID: qhWKngVT4
Submitter: Connie Wang
Submission Date: July 31, 2017, 11:46 a.m.
Version: 1
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Structure ID | Release Date | Resolution | Structure Title |
---|---|---|---|
4GAG | 2012-07-25T00:00:00+0000 | 1.8 | Structure of the broadly neutralizing antibody AP33 in complex with its HCV epitope (E2 residues 412-423) |
5VXR | 2017-05-24T00:00:00+0000 | 1.4 | The antigen-binding fragment of MAb24 in complex with a peptide from Hepatitis C Virus E2 epitope I (412-423) |
2KNU | 2009-09-04T00:00:00+0000 | 0 | Solution structure of the transmembrane proximal region of the hepatis C virus E1 glycoprotein |
3MRG | 2010-04-29T00:00:00+0000 | 1.3 | Crystal Structure of MHC class I HLA-A2 molecule complexed with HCV NS3-1073-1081 nonapeptide |
3MRH | 2010-04-29T00:00:00+0000 | 2.4 | Crystal Structure of MHC class I HLA-A2 molecule complexed with HCV NS3-1073-1081 nonapeptide N3S variant |
3MRI | 2010-04-29T00:00:00+0000 | 2.1 | Crystal Structure of MHC class I HLA-A2 molecule complexed with HCV NS3-1073-1081 nonapeptide G4M-V5W variant |
3MRJ | 2010-04-29T00:00:00+0000 | 1.87 | Crystal Structure of MHC class I HLA-A2 molecule complexed with HCV NS3-1073-1081 nonapeptide V5M variant |
3MRL | 2010-04-29T00:00:00+0000 | 2.41 | Crystal Structure of MHC class I HLA-A2 molecule complexed with HCV NS3-1073-1081 nonapeptide C6V variant |
1RTL | 2003-12-10T00:00:00+0000 | 2.75 | CRYSTAL STRUCTURE OF HCV NS3 PROTEASE DOMAIN: NS4A PEPTIDE COMPLEX WITH COVALENTLY BOUND PYRROLIDINE-5,5-TRANSLACTAM INHIBITOR |
2A4G | 2005-06-28T00:00:00+0000 | 2.5 | Hepatitis C Protease NS3-4A serine protease with Ketoamide Inhibitor SCH225724 Bound |
Percent Identity | Matching Chains | Protein | Accession | Entry Name |
---|---|---|---|---|
100.0 | hepatitis C virus E2 glycoprotein | P27958 | POLG_HCVH | |
95.9 | hepatitis C virus E2 glycoprotein | P26664 | POLG_HCV1 | |
95.2 | hepatitis C virus E2 glycoprotein | Q03463 | POLG_HCVJ1 | |
93.4 | hepatitis C virus E2 glycoprotein | Q5EG65 | POLG_HCVGL | |
92.2 | hepatitis C virus E2 glycoprotein | P27956 | POLG_HCVH8 | |
91.3 | hepatitis C virus E2 glycoprotein | P27957 | POLG_HCVTH | |
90.3 | hepatitis C virus E2 glycoprotein | P27955 | POLG_HCVH7 | |
96.9 | hepatitis C virus E2 glycoprotein | P27954 | POLG_HCVE1 |