Peptide Triazole
Inactivators of HIV‑1 Utilize
a Conserved Two-Cavity Binding Site at the Junction of the Inner and
Outer Domains of Env gp120
- Publication date
- Publisher
Abstract
We
used coordinated mutagenesis, synthetic design, and flexible
docking to investigate the structural mechanism of Env gp120 encounter
by peptide triazole (PT) inactivators of HIV-1. Prior results demonstrated
that the PT class of inhibitors suppresses binding at both CD4 and
coreceptor sites on Env and triggers gp120 shedding, leading to cell-independent
irreversible virus inactivation. Despite these enticing anti-HIV-1
phenotypes, structural understanding of the PT–gp120 binding
mechanism has been incomplete. Here we found that PT engages two inhibitor
ring moieties at the junction between the inner and outer domains
of the gp120 protein. The results demonstrate how combined occupancy
of two gp120 cavities can coordinately suppress both receptor and
coreceptor binding and conformationally entrap the protein in a destabilized
state. The two-cavity model has common features with small molecule
gp120 inhibitor binding sites and provides a guide for further design
of peptidomimetic HIV-1 inactivators based on the PT pharmacophore