The β20-β21 of gp120 is a regulatory switch for HIV-1 Env conformational transitions.
Alon HerschhornChristopher GuFrancesca MoracaXiaochu MaMark FarrellAmos B SmithMarie PanceraPeter D KwongArne SchönErnesto FreireCameron F AbramsScott C BlanchardWalther MothesJoseph G SodroskiPublished in: Nature communications (2017)
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.
Keyphrases
- antiretroviral therapy
- hiv positive
- hiv infected
- hiv testing
- human immunodeficiency virus
- hepatitis c virus
- hiv aids
- single molecule
- induced apoptosis
- men who have sex with men
- molecular dynamics
- molecular dynamics simulations
- cell cycle arrest
- small molecule
- amino acid
- minimally invasive
- south africa
- climate change
- risk assessment
- endoplasmic reticulum stress
- cell death
- machine learning
- cell proliferation
- binding protein
- living cells
- artificial intelligence