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

Alon Herschhorn; Christopher Gu; Francesca Moraca; Xiaochu Ma; Mark Farrell; Amos B. Smith; Marie Pancera; Peter D. Kwong; Arne Schön; Ernesto Freire; Cameron Abrams; Scott C. Blanchard; Walther Mothes; Joseph G. Sodroski

doi:10.1038/s41467-017-01119-w

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

Alon Herschhorn, Christopher Gu, Francesca Moraca, Xiaochu Ma, Mark Farrell, Amos B. Smith, Marie Pancera, Peter D. Kwong, Arne Schön, Ernesto Freire, Cameron Abrams, Scott C. Blanchard, Walther Mothes, Joseph G. Sodroski

School of Medicine

Research output: Contribution to journal › Article › peer-review

36 Scopus citations

Abstract

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.

Original language	English (US)
Article number	1049
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-01119-w
State	Published - Dec 1 2017

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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title = "The β20-β21 of gp120 is a regulatory switch for HIV-1 Env conformational transitions",

abstract = "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.",

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doi = "10.1038/s41467-017-01119-w",

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AU - Herschhorn, Alon

AU - Gu, Christopher

AU - Moraca, Francesca

AU - Ma, Xiaochu

AU - Farrell, Mark

AU - Smith, Amos B.

AU - Pancera, Marie

AU - Kwong, Peter D.

AU - Schön, Arne

AU - Freire, Ernesto

AU - Abrams, Cameron

AU - Blanchard, Scott C.

AU - Mothes, Walther

AU - Sodroski, Joseph G.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

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

Abstract

ASJC Scopus subject areas

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