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

The β20-β21 of gp120 is a regulatory switch for HIV-1 Env conformational transitions.
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Herschhorn A, Gu C, Moraca F, Ma X, Farrell M, Smith AB, Pancera M, Kwong PD, Schön A, Freire E, Abrams C, Blanchard SC, Mothes W, Sodroski JG,


Herschhorn A, Gu C, Moraca F, Ma X, Farrell M, Smith AB, Pancera M, Kwong PD, Schön A, Freire E, Abrams C, Blanchard SC, Mothes W, Sodroski JG, (click to view)

Herschhorn A, Gu C, Moraca F, Ma X, Farrell M, Smith AB, Pancera M, Kwong PD, Schön A, Freire E, Abrams C, Blanchard SC, Mothes W, Sodroski JG,

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Nature communications 2017 10 198(1) 1049 doi 10.1038/s41467-017-01119-w

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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