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Title: Structure of Hepatitis C virus envelope glycoprotein E1 antigenic site 314–324 in complex with antibody IGH526

Hepatitis C virus (HCV) is a positive-strand RNA virus within the Flaviviridae family. The viral “spike” of HCV is formed by two envelope glycoproteins, E1 and E2, which together mediate viral entry by engaging host receptors and undergoing conformational changes to facilitate membrane fusion. While E2 can be readily produced in the absence of E1, E1 cannot be expressed without E2 and few reagents, including monoclonal antibodies, are available for study of this essential HCV glycoprotein. A human MAb to E1, IGH526, was previously reported to cross-neutralize different HCV isolates and, therefore, we sought to further characterize the IGH526 neutralizing epitope to obtain information for vaccine design. Here, we found that MAb IGH526 bound to a discontinuous epitope, but with a major component corresponding to E1 residues 314-324. The crystal structure of IGH526 Fab with this E1 glycopeptide at 1.75Å resolution revealed that the antibody binds to one face of an α-helical peptide. Single mutations on the helix substantially lowered IGH526 binding but did not affect neutralization, indicating either that multiple mutations are required or that additional regions are recognized by the antibody in the context of the membrane-associated envelope oligomer. Finally, molecular dynamics simulations indicate the free peptide ismore » flexible in solution, suggesting that it requires stabilization for use as a candidate vaccine immunogen.« less
Authors:
 [1] ;  [1] ;  [2] ;  [2] ;  [1] ;  [3] ;  [1] ;  [4] ;  [5] ;  [2]
  1. The Scripps Research Inst., La Jolla, CA (United States). Dept. of Integrative Structural and Computational Biology
  2. The Scripps Research Inst., La Jolla, CA (United States). Dept. of Immunology and Microbial Science
  3. The Scripps Research Inst., La Jolla, CA (United States). Dept. of Chemistry; The Scripps Research Inst., La Jolla, CA (United States). Dept. of Cell and Molecular Biology
  4. The Scripps Research Inst., La Jolla, CA (United States). Dept. of Chemistry; The Scripps Research Inst., La Jolla, CA (United States). Dept. of Cell and Molecular Biology
  5. The Scripps Research Inst., La Jolla, CA (United States). Dept. of Integrative Structural and Computational Biology; The Scripps Research Inst., La Jolla, CA (United States). Skaggs Inst. for Chemical Biology
Publication Date:
OSTI Identifier:
1214858
Grant/Contract Number:
AC02-06CH11357; AI079031; AI106005; AI084817; U54 GM094586
Type:
Accepted Manuscript
Journal Name:
Journal of Molecular Biology
Additional Journal Information:
Journal Volume: 427; Journal Issue: 16; Journal ID: ISSN 0022-2836
Publisher:
Elsevier
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Institutes of Health (NIH)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; HCV; E1 envelope glycoprotein; IGH526; vaccine design