Disruption of the HIV-1 Envelope allosteric network blocks CD4-induced rearrangements.
The trimeric HIV-1 Envelope protein (Env) mediates viral-host cell fusion via a network of conformational transitions, with allosteric elements in each protomer orchestrating host receptor-induced exposure of the co-receptor binding site and fusion elements. To understand the molecular details of this allostery, here, we introduce Env mutations aimed to prevent CD4-induced rearrangements in the HIV-1 BG505 Env trimer. Binding analysis and single-molecule Förster Resonance Energy Transfer confirm that these mutations prevent CD4-induced transitions of the HIV-1 Env. Structural analysis by single-particle cryo-electron microscopy performed on the BG505 SOSIP mutant Env proteins shows rearrangements in the gp120 topological layer contacts with gp41. Displacement of a conserved tryptophan (W571) from its typical pocket in these Env mutants renders the Env insensitive to CD4 binding. These results reveal the critical function of W571 as a conformational switch in Env allostery and receptor-mediated viral entry and provide insights on Env conformation that are relevant for vaccine design.
Henderson, R; Lu, M; Zhou, Y; Mu, Z; Parks, R; Han, Q; Hsu, AL; Carter, E; Blanchard, SC; Edwards, RJ; Wiehe, K; Saunders, KO; Borgnia, MJ; Bartesaghi, A; Mothes, W; Haynes, BF; Acharya, P; Munir Alam, S
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