Crystal structure of the neutralizing Llama V(HH) D7 and its mode of HIV-1 gp120 interaction.

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,...

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Autores principales: Andreas Hinz, David Lutje Hulsik, Anna Forsman, Willie Wee-Lee Koh, Hassan Belrhali, Andrea Gorlani, Hans de Haard, Robin A Weiss, Theo Verrips, Winfried Weissenhorn
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Publicado: Public Library of Science (PLoS) 2010
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spelling oai:doaj.org-article:cc4438b984d14872b7496273180a0aa02021-12-02T20:21:54ZCrystal structure of the neutralizing Llama V(HH) D7 and its mode of HIV-1 gp120 interaction.1932-620310.1371/journal.pone.0010482https://doaj.org/article/cc4438b984d14872b7496273180a0aa02010-05-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20463957/?tool=EBIhttps://doaj.org/toc/1932-6203HIV-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 A 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.Andreas HinzDavid Lutje HulsikAnna ForsmanWillie Wee-Lee KohHassan BelrhaliAndrea GorlaniHans de HaardRobin A WeissTheo VerripsWinfried WeissenhornPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 5, p e10482 (2010)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Andreas Hinz
David Lutje Hulsik
Anna Forsman
Willie Wee-Lee Koh
Hassan Belrhali
Andrea Gorlani
Hans de Haard
Robin A Weiss
Theo Verrips
Winfried Weissenhorn
Crystal structure of the neutralizing Llama V(HH) D7 and its mode of HIV-1 gp120 interaction.
description 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 A 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.
format article
author Andreas Hinz
David Lutje Hulsik
Anna Forsman
Willie Wee-Lee Koh
Hassan Belrhali
Andrea Gorlani
Hans de Haard
Robin A Weiss
Theo Verrips
Winfried Weissenhorn
author_facet Andreas Hinz
David Lutje Hulsik
Anna Forsman
Willie Wee-Lee Koh
Hassan Belrhali
Andrea Gorlani
Hans de Haard
Robin A Weiss
Theo Verrips
Winfried Weissenhorn
author_sort Andreas Hinz
title Crystal structure of the neutralizing Llama V(HH) D7 and its mode of HIV-1 gp120 interaction.
title_short Crystal structure of the neutralizing Llama V(HH) D7 and its mode of HIV-1 gp120 interaction.
title_full Crystal structure of the neutralizing Llama V(HH) D7 and its mode of HIV-1 gp120 interaction.
title_fullStr Crystal structure of the neutralizing Llama V(HH) D7 and its mode of HIV-1 gp120 interaction.
title_full_unstemmed Crystal structure of the neutralizing Llama V(HH) D7 and its mode of HIV-1 gp120 interaction.
title_sort crystal structure of the neutralizing llama v(hh) d7 and its mode of hiv-1 gp120 interaction.
publisher Public Library of Science (PLoS)
publishDate 2010
url https://doaj.org/article/cc4438b984d14872b7496273180a0aa0
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