U.S. Department of EnergyOffice of Scientific and Technical Information
Structural Basis of HIV-1 Neutralization by Affinity Matured Fabs Directed against the Internal Trimeric Coiled-Coil of gp41
Abstract
The conserved internal trimeric coiled-coil of the N-heptad repeat (N-HR) of HIV-1 gp41 is transiently exposed during the fusion process by forming a pre-hairpin intermediate, thus representing an attractive target for the design of fusion inhibitors and neutralizing antibodies. In previous studies we reported a series of broadly neutralizing mini-antibodies derived from a synthetic naive human combinatorial antibody library by panning against a mimetic of the trimeric N-HR coiled coil, followed by affinity maturation using targeted diversification of the CDR-H2 loop. Here we report crystal structures of the N-HR mimetic 5-Helix with two Fabs that represent the extremes of this series: Fab 8066 is broadly neutralizing across a wide panel of B and C type HIV-1 viruses, whereas Fab 8062 is non-neutralizing. The crystal structures reveal important differences in the conformations of the CDR-H2 loops in the complexes that propagate into other regions of the antigen-antibody interface, and suggest that both neutralization properties and affinity for the target can be attributed, at least in part, to the differences in the interactions of the CDR-H2 loops with the antigen. Furthermore, modeling of the complex of an N-HR trimer with three Fabs suggests that the CDR-H2 loop may be involved in closemore »
- Authors:
-
- NIH
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1002908
- Resource Type:
- Journal Article
- Journal Name:
- PLoS Patho.
- Additional Journal Information:
- Journal Volume: 6; Journal Issue: (11) ; 2010
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 36 MATERIALS SCIENCE; AFFINITY; ANTIBODIES; CONVERGENCE; CRYSTAL STRUCTURE; DESIGN; DIVERSIFICATION; SIMULATION; TARGETS; VIRUSES
Citation Formats
Gustchina, Elena, Li, Mi, Louis, John M, Anderson, D Eric, Lloyd, John, Frisch, Christian, Bewley, Carole A, Gustchina, Alla, Wlodawer, Alexander, Clore, G Marius, NCI), and AbD Serotec). Structural Basis of HIV-1 Neutralization by Affinity Matured Fabs Directed against the Internal Trimeric Coiled-Coil of gp41. United States: N. p., 2010.
Web. doi:10.1371/journal.ppat.1001182.
Gustchina, Elena, Li, Mi, Louis, John M, Anderson, D Eric, Lloyd, John, Frisch, Christian, Bewley, Carole A, Gustchina, Alla, Wlodawer, Alexander, Clore, G Marius, NCI), & AbD Serotec). Structural Basis of HIV-1 Neutralization by Affinity Matured Fabs Directed against the Internal Trimeric Coiled-Coil of gp41. United States. https://doi.org/10.1371/journal.ppat.1001182
Gustchina, Elena, Li, Mi, Louis, John M, Anderson, D Eric, Lloyd, John, Frisch, Christian, Bewley, Carole A, Gustchina, Alla, Wlodawer, Alexander, Clore, G Marius, NCI), and AbD Serotec). 2010.
"Structural Basis of HIV-1 Neutralization by Affinity Matured Fabs Directed against the Internal Trimeric Coiled-Coil of gp41". United States. https://doi.org/10.1371/journal.ppat.1001182.
@article{osti_1002908,
title = {Structural Basis of HIV-1 Neutralization by Affinity Matured Fabs Directed against the Internal Trimeric Coiled-Coil of gp41},
author = {Gustchina, Elena and Li, Mi and Louis, John M and Anderson, D Eric and Lloyd, John and Frisch, Christian and Bewley, Carole A and Gustchina, Alla and Wlodawer, Alexander and Clore, G Marius and NCI) and AbD Serotec)},
abstractNote = {The conserved internal trimeric coiled-coil of the N-heptad repeat (N-HR) of HIV-1 gp41 is transiently exposed during the fusion process by forming a pre-hairpin intermediate, thus representing an attractive target for the design of fusion inhibitors and neutralizing antibodies. In previous studies we reported a series of broadly neutralizing mini-antibodies derived from a synthetic naive human combinatorial antibody library by panning against a mimetic of the trimeric N-HR coiled coil, followed by affinity maturation using targeted diversification of the CDR-H2 loop. Here we report crystal structures of the N-HR mimetic 5-Helix with two Fabs that represent the extremes of this series: Fab 8066 is broadly neutralizing across a wide panel of B and C type HIV-1 viruses, whereas Fab 8062 is non-neutralizing. The crystal structures reveal important differences in the conformations of the CDR-H2 loops in the complexes that propagate into other regions of the antigen-antibody interface, and suggest that both neutralization properties and affinity for the target can be attributed, at least in part, to the differences in the interactions of the CDR-H2 loops with the antigen. Furthermore, modeling of the complex of an N-HR trimer with three Fabs suggests that the CDR-H2 loop may be involved in close intermolecular contacts between neighboring antibody molecules, and that such contacts may hinder the formation of complexes between the N-HR trimer and more than one antibody molecule depending on the conformation of the bound CDR-H2 loop which is defined by its interactions with antigen. Comparison with the crystal structure of the complex of 5-Helix with another neutralizing monoclonal antibody known as D5, derived using an entirely different antibody library and panning procedure, reveals remarkable convergence in the optimal sequence and conformation of the CDR-H2 loop.},
doi = {10.1371/journal.ppat.1001182},
url = {https://www.osti.gov/biblio/1002908},
journal = {PLoS Patho.},
number = (11) ; 2010,
volume = 6,
place = {United States},
year = {Fri Dec 03 00:00:00 EST 2010},
month = {Fri Dec 03 00:00:00 EST 2010}
}
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