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Open and Closed Structures Reveal Allostery and Pliability in the HIV-1 Envelope Spike
For many enveloped viruses, binding to a receptor(s) on a host cell acts as a first step in a series of events culminating in fusion with the host cell membrane and transfer of genetic material for replication [for review see(1,2)]. The envelope glycoprotein (Env) trimer on the surface of HIV is res...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538736/ https://www.ncbi.nlm.nih.gov/pubmed/28700571 http://dx.doi.org/10.1038/nature23010 |
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author | Ozorowski, Gabriel Pallesen, Jesper de Val, Natalia Lyumkis, Dmitry Cottrell, Christopher A. Torres, Jonathan L. Copps, Jeffrey Stanfield, Robyn L. Cupo, Albert Pugach, Pavel Moore, John P. Wilson, Ian A. Ward, Andrew B. |
author_facet | Ozorowski, Gabriel Pallesen, Jesper de Val, Natalia Lyumkis, Dmitry Cottrell, Christopher A. Torres, Jonathan L. Copps, Jeffrey Stanfield, Robyn L. Cupo, Albert Pugach, Pavel Moore, John P. Wilson, Ian A. Ward, Andrew B. |
author_sort | Ozorowski, Gabriel |
collection | PubMed |
description | For many enveloped viruses, binding to a receptor(s) on a host cell acts as a first step in a series of events culminating in fusion with the host cell membrane and transfer of genetic material for replication [for review see(1,2)]. The envelope glycoprotein (Env) trimer on the surface of HIV is responsible for receptor binding and fusion. While Env can tolerate a high degree of mutation in five variable regions (V1-V5), and also at N-linked glycosylation sites that contribute roughly half the mass of Env, the functional sites for recognition of receptor CD4 and co-receptor CXCR4/CCR5 are conserved and essential for viral fitness. Soluble SOSIP Env trimers are structural and antigenic mimics of the pre-fusion native, surface-presented Env(3,4), targets of broadly neutralizing antibodies (bnAbs). Thus, they are attractive immunogens for vaccine development [for review see(5–8)]. Here we present high-resolution cryo-electron microscopy (cryoEM) structures of subtype B B41 SOSIP Env trimers in complex with CD4 and antibody 17b, or with antibody b12, at resolutions of ~3.7 Å and ~3.6 Å, respectively, and compare them to cryoEM reconstructions of ligand-free B41 SOSIP Env trimers or in complex with either CD4 or CD4bs antibody PGV04, at ~5.6 Å, ~5.2 Å and ~7.4 Å, respectively. Consequently, we present the most complete description and understanding of the CD4/17b-induced intermediate and provide the molecular basis of the receptor-binding induced conformational change required for HIV-1 entry into host cells. Both CD4 and b12 induce large, previously uncharacterized conformational rearrangements in the gp41 subunits, and the fusion peptide becomes more buried in a newly formed pocket. These structures provide key details on the biological function of the type I viral fusion machine from HIV-1 as well as new templates for inhibitor design. |
format | Online Article Text |
id | pubmed-5538736 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
record_format | MEDLINE/PubMed |
spelling | pubmed-55387362018-01-12 Open and Closed Structures Reveal Allostery and Pliability in the HIV-1 Envelope Spike Ozorowski, Gabriel Pallesen, Jesper de Val, Natalia Lyumkis, Dmitry Cottrell, Christopher A. Torres, Jonathan L. Copps, Jeffrey Stanfield, Robyn L. Cupo, Albert Pugach, Pavel Moore, John P. Wilson, Ian A. Ward, Andrew B. Nature Article For many enveloped viruses, binding to a receptor(s) on a host cell acts as a first step in a series of events culminating in fusion with the host cell membrane and transfer of genetic material for replication [for review see(1,2)]. The envelope glycoprotein (Env) trimer on the surface of HIV is responsible for receptor binding and fusion. While Env can tolerate a high degree of mutation in five variable regions (V1-V5), and also at N-linked glycosylation sites that contribute roughly half the mass of Env, the functional sites for recognition of receptor CD4 and co-receptor CXCR4/CCR5 are conserved and essential for viral fitness. Soluble SOSIP Env trimers are structural and antigenic mimics of the pre-fusion native, surface-presented Env(3,4), targets of broadly neutralizing antibodies (bnAbs). Thus, they are attractive immunogens for vaccine development [for review see(5–8)]. Here we present high-resolution cryo-electron microscopy (cryoEM) structures of subtype B B41 SOSIP Env trimers in complex with CD4 and antibody 17b, or with antibody b12, at resolutions of ~3.7 Å and ~3.6 Å, respectively, and compare them to cryoEM reconstructions of ligand-free B41 SOSIP Env trimers or in complex with either CD4 or CD4bs antibody PGV04, at ~5.6 Å, ~5.2 Å and ~7.4 Å, respectively. Consequently, we present the most complete description and understanding of the CD4/17b-induced intermediate and provide the molecular basis of the receptor-binding induced conformational change required for HIV-1 entry into host cells. Both CD4 and b12 induce large, previously uncharacterized conformational rearrangements in the gp41 subunits, and the fusion peptide becomes more buried in a newly formed pocket. These structures provide key details on the biological function of the type I viral fusion machine from HIV-1 as well as new templates for inhibitor design. 2017-07-12 2017-07-20 /pmc/articles/PMC5538736/ /pubmed/28700571 http://dx.doi.org/10.1038/nature23010 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms Reprints and permissions information is available at www.nature.com/reprints. |
spellingShingle | Article Ozorowski, Gabriel Pallesen, Jesper de Val, Natalia Lyumkis, Dmitry Cottrell, Christopher A. Torres, Jonathan L. Copps, Jeffrey Stanfield, Robyn L. Cupo, Albert Pugach, Pavel Moore, John P. Wilson, Ian A. Ward, Andrew B. Open and Closed Structures Reveal Allostery and Pliability in the HIV-1 Envelope Spike |
title | Open and Closed Structures Reveal Allostery and Pliability in the HIV-1 Envelope Spike |
title_full | Open and Closed Structures Reveal Allostery and Pliability in the HIV-1 Envelope Spike |
title_fullStr | Open and Closed Structures Reveal Allostery and Pliability in the HIV-1 Envelope Spike |
title_full_unstemmed | Open and Closed Structures Reveal Allostery and Pliability in the HIV-1 Envelope Spike |
title_short | Open and Closed Structures Reveal Allostery and Pliability in the HIV-1 Envelope Spike |
title_sort | open and closed structures reveal allostery and pliability in the hiv-1 envelope spike |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538736/ https://www.ncbi.nlm.nih.gov/pubmed/28700571 http://dx.doi.org/10.1038/nature23010 |
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