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Title: Structure-Based Design of a Protein Immunogen that Displays an HIV-1 gp41 Neutralizing Epitope

Abstract

Antibody Z13e1 is a relatively broadly neutralizing anti-human immunodeficiency virus type 1 antibody that recognizes the membrane-proximal external region (MPER) of the human immunodeficiency virus type 1 envelope glycoprotein gp41. Based on the crystal structure of an MPER epitope peptide in complex with Z13e1 Fab, we identified an unrelated protein, interleukin (IL)-22, with a surface-exposed region that is structurally homologous in its backbone to the gp41 Z13e1 epitope. By grafting the gp41 Z13e1 epitope sequence onto the structurally homologous region in IL-22, we engineered a novel protein (Z13-IL22-2) that contains the MPER epitope sequence for use as a potential immunogen and as a reagent for the detection of Z13e1-like antibodies. The Z13-IL22-2 protein binds Fab Z13e1 with a K{sub d} of 73 nM. The crystal structure of Z13-IL22-2 in complex with Fab Z13e1 shows that the epitope region is faithfully replicated in the Fab-bound scaffold protein; however, isothermal calorimetry studies indicate that Fab binding to Z13-IL22-2 is not a lock-and-key event, leaving open the question of whether conformational changes upon binding occur in the Fab, in Z13-IL-22, or in both.

Authors:
; ; ; ; ;  [1]
  1. (Scripps)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
OTHERFOREIGNNIH
OSTI Identifier:
1041344
Resource Type:
Journal Article
Journal Name:
J. Mol. Biol.
Additional Journal Information:
Journal Volume: 414; Journal Issue: (3) ; 12, 2011; Journal ID: ISSN 0022-2836
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; AIDS VIRUS; ANTIBODIES; CALORIMETRY; CONFORMATIONAL CHANGES; CRYSTAL STRUCTURE; DESIGN; DETECTION; GLYCOPROTEINS; LYMPHOKINES; PEPTIDES; PROTEINS

Citation Formats

Stanfield, Robyn L., Julien, Jean-Philippe, Pejchal, Robert, Gach, Johannes S., Zwick, Michael B., and Wilson, Ian A. Structure-Based Design of a Protein Immunogen that Displays an HIV-1 gp41 Neutralizing Epitope. United States: N. p., 2012. Web. doi:10.1016/j.jmb.2011.10.014.
Stanfield, Robyn L., Julien, Jean-Philippe, Pejchal, Robert, Gach, Johannes S., Zwick, Michael B., & Wilson, Ian A. Structure-Based Design of a Protein Immunogen that Displays an HIV-1 gp41 Neutralizing Epitope. United States. doi:10.1016/j.jmb.2011.10.014.
Stanfield, Robyn L., Julien, Jean-Philippe, Pejchal, Robert, Gach, Johannes S., Zwick, Michael B., and Wilson, Ian A. Wed . "Structure-Based Design of a Protein Immunogen that Displays an HIV-1 gp41 Neutralizing Epitope". United States. doi:10.1016/j.jmb.2011.10.014.
@article{osti_1041344,
title = {Structure-Based Design of a Protein Immunogen that Displays an HIV-1 gp41 Neutralizing Epitope},
author = {Stanfield, Robyn L. and Julien, Jean-Philippe and Pejchal, Robert and Gach, Johannes S. and Zwick, Michael B. and Wilson, Ian A.},
abstractNote = {Antibody Z13e1 is a relatively broadly neutralizing anti-human immunodeficiency virus type 1 antibody that recognizes the membrane-proximal external region (MPER) of the human immunodeficiency virus type 1 envelope glycoprotein gp41. Based on the crystal structure of an MPER epitope peptide in complex with Z13e1 Fab, we identified an unrelated protein, interleukin (IL)-22, with a surface-exposed region that is structurally homologous in its backbone to the gp41 Z13e1 epitope. By grafting the gp41 Z13e1 epitope sequence onto the structurally homologous region in IL-22, we engineered a novel protein (Z13-IL22-2) that contains the MPER epitope sequence for use as a potential immunogen and as a reagent for the detection of Z13e1-like antibodies. The Z13-IL22-2 protein binds Fab Z13e1 with a K{sub d} of 73 nM. The crystal structure of Z13-IL22-2 in complex with Fab Z13e1 shows that the epitope region is faithfully replicated in the Fab-bound scaffold protein; however, isothermal calorimetry studies indicate that Fab binding to Z13-IL22-2 is not a lock-and-key event, leaving open the question of whether conformational changes upon binding occur in the Fab, in Z13-IL-22, or in both.},
doi = {10.1016/j.jmb.2011.10.014},
journal = {J. Mol. Biol.},
issn = {0022-2836},
number = (3) ; 12, 2011,
volume = 414,
place = {United States},
year = {2012},
month = {6}
}