A novel HIV-1 inhibitor blocks ubiquitin recognition by Tsg101

Authors

• M Strickland
• LS Ehrlich
• S Watanabe
• M Khan
• M-P Strub
• EJ Seo
• MD Powell
• J Leis
• C Carter
• N Tjandra

Abstract

Proton pump inhibitors (PPIs) are traditionally used to treat gastrointestinal bleeding, stomach ulcers, and acid reflux. Recently, high-throughput small-molecule screening also identified these compounds as potent inhibitors of HIV-1, the causative agent of AIDS. The inhibitors cause viral particles to become tethered to the surface of an infected cell, preventing their release to infect other cells. We identified the human protein Tsg101 as the target for these compounds. Tsg101 is a component of the vesicular trafficking machinery in the cell and is known to be hijacked by HIV-1 Gag to release the budding HIV-1 particle. In order to develop improved versions of the drugs tailored to the treatment of HIV-1, and to further understand the mechanism of inhibition, we determined the high-resolution structure of Tsg101 with one of the inhibitors identified in the screen using NMR spectroscopy. We identified the target of the inhibitor as the ubiquitin recognition site of Tsg101, which led us to a new model for the recruitment of Tsg101 by Gag and a completely new target for HIV-1 inhibition. We also used a suite of specialized NMR techniques designed to probe the nature of the interaction in order to generate an atomic-resolution structure of the Tsg101-inhibitor complex. A high quality structure such as this is necessary for the future design of an improved drug and provides us with an exciting opportunity to develop this novel class of HIV-1 inhibitors.

Scientific Focus Area: Structural Biology

This page was last updated on Friday, March 26, 2021