National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
1R01AI145687-01
United States
Citation
Journal: Nat Commun / Year: 2020 Title: Disruption of the HIV-1 Envelope allosteric network blocks CD4-induced rearrangements. Authors: Rory Henderson / Maolin Lu / Ye Zhou / Zekun Mu / Robert Parks / Qifeng Han / Allen L Hsu / Elizabeth Carter / Scott C Blanchard / R J Edwards / Kevin Wiehe / Kevin O Saunders / Mario J ...Authors: Rory Henderson / Maolin Lu / Ye Zhou / Zekun Mu / Robert Parks / Qifeng Han / Allen L Hsu / Elizabeth Carter / Scott C Blanchard / R J Edwards / Kevin Wiehe / Kevin O Saunders / Mario J Borgnia / Alberto Bartesaghi / Walther Mothes / Barton F Haynes / Priyamvada Acharya / S Munir Alam / Abstract: 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 ...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.
History
Deposition
Dec 12, 2019
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Header (metadata) release
Feb 5, 2020
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Map release
Feb 5, 2020
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Update
Jul 29, 2020
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Current status
Jul 29, 2020
Processing site: RCSB / Status: Released
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