Elucidation of New Binding Interactions with the Human Tsg101 Protein Using Modified HIV-1 Gag-p6 Derived Peptide Ligands

Abstract

Targeting protein−protein interactions is gaining greater recognition as an attractive approach to therapeutic development. An example of this may be found with the human cellular protein encoded by the tumor susceptibility gene 101 (Tsg101), where interaction with the p6 C-terminal domain of the nascent viral Gag protein is required for HIV-1 particle budding and release. This association of Gag with Tsg101 is highly dependent on a “Pro-Thr-Ala-Pro” (“PTAP”) peptide sequence within the p6 protein. Although p6-derived peptides offer potential starting points for developing Tsg101-binding inhibitors, the affinities of canonical peptides are outside the useful range (Kd values greater than 50 μM). Reported herein are crystal structures of Tsg101 in complex with two structurally modified PTAP-derived peptides. These data define new regions of ligand interaction not previously identified with canonical peptide sequences. This information could be highly useful in the design of Tsg101-binding antagonists