Cargando…

The β20–β21 of gp120 is a regulatory switch for HIV-1 Env conformational transitions

The entry of HIV-1 into target cells is mediated by the viral envelope glycoproteins (Env). Binding to the CD4 receptor triggers a cascade of conformational changes in distant domains that move Env from a functionally “closed” State 1 to more “open” conformations, but the molecular mechanisms underl...

Descripción completa

Detalles Bibliográficos
Autores principales: Herschhorn, Alon, Gu, Christopher, Moraca, Francesca, Ma, Xiaochu, Farrell, Mark, Smith, Amos B., Pancera, Marie, Kwong, Peter D., Schön, Arne, Freire, Ernesto, Abrams, Cameron, Blanchard, Scott C., Mothes, Walther, Sodroski, Joseph G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648922/
https://www.ncbi.nlm.nih.gov/pubmed/29051495
http://dx.doi.org/10.1038/s41467-017-01119-w
_version_ 1783272467609944064
author Herschhorn, Alon
Gu, Christopher
Moraca, Francesca
Ma, Xiaochu
Farrell, Mark
Smith, Amos B.
Pancera, Marie
Kwong, Peter D.
Schön, Arne
Freire, Ernesto
Abrams, Cameron
Blanchard, Scott C.
Mothes, Walther
Sodroski, Joseph G.
author_facet Herschhorn, Alon
Gu, Christopher
Moraca, Francesca
Ma, Xiaochu
Farrell, Mark
Smith, Amos B.
Pancera, Marie
Kwong, Peter D.
Schön, Arne
Freire, Ernesto
Abrams, Cameron
Blanchard, Scott C.
Mothes, Walther
Sodroski, Joseph G.
author_sort Herschhorn, Alon
collection PubMed
description The entry of HIV-1 into target cells is mediated by the viral envelope glycoproteins (Env). Binding to the CD4 receptor triggers a cascade of conformational changes in distant domains that move Env from a functionally “closed” State 1 to more “open” conformations, but the molecular mechanisms underlying allosteric regulation of these transitions are still elusive. Here, we develop chemical probes that block CD4-induced conformational changes in Env and use them to identify a potential control switch for Env structural rearrangements. We identify the gp120 β20–β21 element as a major regulator of Env transitions. Several amino acid changes in the β20–β21 base lead to open Env conformations, recapitulating the structural changes induced by CD4 binding. These HIV-1 mutants require less CD4 to infect cells and are relatively resistant to State 1-preferring broadly neutralizing antibodies. These data provide insights into the molecular mechanism and vulnerability of HIV-1 entry.
format Online
Article
Text
id pubmed-5648922
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-56489222017-10-23 The β20–β21 of gp120 is a regulatory switch for HIV-1 Env conformational transitions Herschhorn, Alon Gu, Christopher Moraca, Francesca Ma, Xiaochu Farrell, Mark Smith, Amos B. Pancera, Marie Kwong, Peter D. Schön, Arne Freire, Ernesto Abrams, Cameron Blanchard, Scott C. Mothes, Walther Sodroski, Joseph G. Nat Commun Article The entry of HIV-1 into target cells is mediated by the viral envelope glycoproteins (Env). Binding to the CD4 receptor triggers a cascade of conformational changes in distant domains that move Env from a functionally “closed” State 1 to more “open” conformations, but the molecular mechanisms underlying allosteric regulation of these transitions are still elusive. Here, we develop chemical probes that block CD4-induced conformational changes in Env and use them to identify a potential control switch for Env structural rearrangements. We identify the gp120 β20–β21 element as a major regulator of Env transitions. Several amino acid changes in the β20–β21 base lead to open Env conformations, recapitulating the structural changes induced by CD4 binding. These HIV-1 mutants require less CD4 to infect cells and are relatively resistant to State 1-preferring broadly neutralizing antibodies. These data provide insights into the molecular mechanism and vulnerability of HIV-1 entry. Nature Publishing Group UK 2017-10-19 /pmc/articles/PMC5648922/ /pubmed/29051495 http://dx.doi.org/10.1038/s41467-017-01119-w Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Herschhorn, Alon
Gu, Christopher
Moraca, Francesca
Ma, Xiaochu
Farrell, Mark
Smith, Amos B.
Pancera, Marie
Kwong, Peter D.
Schön, Arne
Freire, Ernesto
Abrams, Cameron
Blanchard, Scott C.
Mothes, Walther
Sodroski, Joseph G.
The β20–β21 of gp120 is a regulatory switch for HIV-1 Env conformational transitions
title The β20–β21 of gp120 is a regulatory switch for HIV-1 Env conformational transitions
title_full The β20–β21 of gp120 is a regulatory switch for HIV-1 Env conformational transitions
title_fullStr The β20–β21 of gp120 is a regulatory switch for HIV-1 Env conformational transitions
title_full_unstemmed The β20–β21 of gp120 is a regulatory switch for HIV-1 Env conformational transitions
title_short The β20–β21 of gp120 is a regulatory switch for HIV-1 Env conformational transitions
title_sort β20–β21 of gp120 is a regulatory switch for hiv-1 env conformational transitions
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648922/
https://www.ncbi.nlm.nih.gov/pubmed/29051495
http://dx.doi.org/10.1038/s41467-017-01119-w
work_keys_str_mv AT herschhornalon theb20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT guchristopher theb20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT moracafrancesca theb20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT maxiaochu theb20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT farrellmark theb20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT smithamosb theb20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT panceramarie theb20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT kwongpeterd theb20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT schonarne theb20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT freireernesto theb20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT abramscameron theb20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT blanchardscottc theb20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT motheswalther theb20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT sodroskijosephg theb20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT herschhornalon b20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT guchristopher b20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT moracafrancesca b20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT maxiaochu b20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT farrellmark b20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT smithamosb b20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT panceramarie b20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT kwongpeterd b20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT schonarne b20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT freireernesto b20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT abramscameron b20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT blanchardscottc b20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT motheswalther b20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions
AT sodroskijosephg b20b21ofgp120isaregulatoryswitchforhiv1envconformationaltransitions