Disruption of the HIV-1 Envelope allosteric network blocks CD4-induced rearrangements. Academic Article uri icon

Overview

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 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.

publication date

  • January 24, 2020

Research

keywords

  • CD4 Antigens
  • HIV-1
  • env Gene Products, Human Immunodeficiency Virus

Identity

PubMed Central ID

  • PMC6981184

Scopus Document Identifier

  • 85078222957

Digital Object Identifier (DOI)

  • 10.1038/nmeth.3769

PubMed ID

  • 31980614

Additional Document Info

volume

  • 11

issue

  • 1