4JZO

Three dimensional structure of broadly neutralizing human anti - Hepatitis C virus (HCV) glycoprotein E2 Fab fragment HC84-27


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.22 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.198 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Structural basis of HCV neutralization by human monoclonal antibodies resistant to viral neutralization escape.

Krey, T.Meola, A.Keck, Z.Y.Damier-Piolle, L.Foung, S.K.Rey, F.A.

(2013) PLoS Pathog 9: e1003364-e1003364

  • DOI: https://doi.org/10.1371/journal.ppat.1003364
  • Primary Citation of Related Structures:  
    4JZN, 4JZO

  • PubMed Abstract: 

    The high mutation rate of hepatitis C virus allows it to rapidly evade the humoral immune response. However, certain epitopes in the envelope glycoproteins cannot vary without compromising virus viability. Antibodies targeting these epitopes are resistant to viral escape from neutralization and understanding their binding-mode is important for vaccine design. Human monoclonal antibodies HC84-1 and HC84-27 target conformational epitopes overlapping the CD81 receptor-binding site, formed by segments aa434-446 and aa610-619 within the major HCV glycoprotein E2. No neutralization escape was yet observed for these antibodies. We report here the crystal structures of their Fab fragments in complex with a synthetic peptide comprising aa434-446. The structures show that the peptide adopts an α-helical conformation with the main contact residues F⁴⁴² and Y⁴⁴³ forming a hydrophobic protrusion. The peptide retained its conformation in both complexes, independently of crystal packing, indicating that it reflects a surface feature of the folded glycoprotein that is exposed similarly on the virion. The same residues of E2 are also involved in interaction with CD81, suggesting that the cellular receptor binds the same surface feature and potential escape mutants critically compromise receptor binding. In summary, our results identify a critical structural motif at the E2 surface, which is essential for virus propagation and therefore represents an ideal candidate for structure-based immunogen design for vaccine development.


  • Organizational Affiliation

    Institut Pasteur, Unité de Virologie Structurale, Departement Virologie, Paris, France. tkrey@pasteur.fr


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Anti-HCV E2 Fab HC84-27 heavy chain
A, C, D, G
261Homo sapiensMutation(s): 0 
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Anti-HCV E2 Fab HC84-27 light chain
B, E, F, H
215Homo sapiensMutation(s): 0 
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  • Reference Sequence

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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Envelope glycoprotein E2
I, J, K, L
13Hepatitis C virus (isolate H)Mutation(s): 0 
EC: 3.4.22 (PDB Primary Data), 3.4.21.98 (PDB Primary Data), 3.6.1.15 (PDB Primary Data), 3.6.4.13 (PDB Primary Data), 2.7.7.48 (PDB Primary Data)
UniProt
Find proteins for P27958 (Hepatitis C virus genotype 1a (isolate H77))
Explore P27958 
Go to UniProtKB:  P27958
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UniProt GroupP27958
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.22 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.198 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 75.94α = 92.1
b = 77.33β = 107.62
c = 85.82γ = 90.24
Software Package:
Software NamePurpose
XDSdata scaling
PHASERphasing
BUSTERrefinement
XDSdata reduction
SCALAdata scaling

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-06-05
    Type: Initial release
  • Version 1.1: 2023-09-20
    Changes: Data collection, Database references, Refinement description