Hinz, A;
Hulsik, DL;
Forsman, A;
Koh, WWL;
Belrhali, H;
Gorlani, A;
de Haard, H;
... Weissenhorn, W; + view all
(2010)
Crystal Structure of the Neutralizing Llama V-HH D7 and Its Mode of HIV-1 gp120 Interaction.
PLOS ONE
, 5
(5)
, Article e10482. 10.1371/journal.pone.0010482.
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Abstract
HIV-1 entry into host cells is mediated by the sequential binding of the envelope glycoprotein gp120 to CD4 and a chemokine receptor. Antibodies binding to epitopes overlapping the CD4-binding site on gp120 are potent inhibitors of HIV entry, such as the llama heavy chain antibody fragment V-HH D7, which has cross-clade neutralizing properties and competes with CD4 and mAb b12 for high affinity binding to gp120. We report the crystal structure of the D7 V-HH at 1.5 angstrom resolution, which reveals the molecular details of the complementarity determining regions (CDR) and substantial flexibility of CDR3 that could facilitate an induced fit interaction with gp120. Structural comparison of CDRs from other CD4 binding site antibodies suggests diverse modes of interaction. Mutational analysis identified CDR3 as a key component of gp120 interaction as determined by surface plasmon resonance. A decrease in affinity is directly coupled to the neutralization efficiency since mutations that decrease gp120 interaction increase the IC50 required for HIV-1 IIIB neutralization. Thus the structural study identifies the long CDR3 of D7 as the key determinant of interaction and HIV-1 neutralization. Furthermore, our data confirm that the structural plasticity of gp120 can accommodate multiple modes of antibody binding within the CD4 binding site.
| Type: | Article |
|---|---|
| Title: | Crystal Structure of the Neutralizing Llama V-HH D7 and Its Mode of HIV-1 gp120 Interaction |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pone.0010482 |
| Publisher version: | http://dx.doi.org/10.1371/journal.pone.0010482 |
| Language: | English |
| Additional information: | © 2010 Hinz et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This work was conducted as part of the Collaboration for AIDS Vaccine Discovery with support from the Bill and Melinda Gates Foundation (to W. W., R. A. W. and T. V.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
| Keywords: | IMMUNODEFICIENCY-VIRUS TYPE-1, HUMAN MONOCLONAL-ANTIBODY, CD4 BINDING-SITE, PROXIMAL EXTERNAL REGION, FUSION INHIBITOR T-20, ENVELOPE GLYCOPROTEIN, SACCHAROMYCES-CEREVISIAE, MEMBRANE-FUSION, HEAVY-CHAIN, GP41 |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
| URI: | https://discovery.ucl.ac.uk/id/eprint/92971 |
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