Structure of Hepatitis C virus envelope glycoprotein E1 antigenic site 314–324 in complex with antibody IGH526
Abstract
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 »
- Authors:
-
- 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). Dept. of Immunology and Microbial Science
- 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
- 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
- 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:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)
- OSTI Identifier:
- 1214858
- Alternate Identifier(s):
- OSTI ID: 1246619
- Grant/Contract Number:
- AC02-06CH11357; AI079031; AI106005; AI084817; U54 GM094586
- Resource 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
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; HCV; E1 envelope glycoprotein; IGH526; vaccine design
Citation Formats
Kong, Leopold, Kadam, Rameshwar U., Giang, Erick, Ruwona, Tinashe B., Nieusma, Travis, Culhane, Jeffrey C., Stanfield, Robyn L., Dawson, Philip E., Wilson, Ian A., and Law, Mansun. Structure of Hepatitis C virus envelope glycoprotein E1 antigenic site 314–324 in complex with antibody IGH526. United States: N. p., 2015.
Web. doi:10.1016/j.jmb.2015.06.012.
Kong, Leopold, Kadam, Rameshwar U., Giang, Erick, Ruwona, Tinashe B., Nieusma, Travis, Culhane, Jeffrey C., Stanfield, Robyn L., Dawson, Philip E., Wilson, Ian A., & Law, Mansun. Structure of Hepatitis C virus envelope glycoprotein E1 antigenic site 314–324 in complex with antibody IGH526. United States. https://doi.org/10.1016/j.jmb.2015.06.012
Kong, Leopold, Kadam, Rameshwar U., Giang, Erick, Ruwona, Tinashe B., Nieusma, Travis, Culhane, Jeffrey C., Stanfield, Robyn L., Dawson, Philip E., Wilson, Ian A., and Law, Mansun. Tue .
"Structure of Hepatitis C virus envelope glycoprotein E1 antigenic site 314–324 in complex with antibody IGH526". United States. https://doi.org/10.1016/j.jmb.2015.06.012. https://www.osti.gov/servlets/purl/1214858.
@article{osti_1214858,
title = {Structure of Hepatitis C virus envelope glycoprotein E1 antigenic site 314–324 in complex with antibody IGH526},
author = {Kong, Leopold and Kadam, Rameshwar U. and Giang, Erick and Ruwona, Tinashe B. and Nieusma, Travis and Culhane, Jeffrey C. and Stanfield, Robyn L. and Dawson, Philip E. and Wilson, Ian A. and Law, Mansun},
abstractNote = {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 is flexible in solution, suggesting that it requires stabilization for use as a candidate vaccine immunogen.},
doi = {10.1016/j.jmb.2015.06.012},
journal = {Journal of Molecular Biology},
number = 16,
volume = 427,
place = {United States},
year = {Tue Jun 30 00:00:00 EDT 2015},
month = {Tue Jun 30 00:00:00 EDT 2015}
}
Web of Science
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