NIH Research Festival
The conjugation of the small ubiquitin-like modifier (SUMO) to protein substrates is an important post-translational modification that has ramifications for cancer and other diseases. As the sole E2 enzyme in the tightly regulated E1/E2/E3 SUMOylation enzymatic cascade, Ubc9 plays a central role in the conjugation of all three SUMO isoforms to a variety of protein targets. Although Ubc9 is viewed as a promising anti-cancer drug target, the development of small-molecule Ubc9 inhibitors has proven to be very difficult. In the past decade, fragment-based drug design has emerged as a powerful approach to identify ligands for challenging protein targets that can provide excellent starting points for the development of potent inhibitors. By X-ray crystallographic fragment screening, we have identified two small-molecule fragments that bind to Ubc9 at a location that is distal from its active site. Although these fragments have weak affinity for Ubc9, biochemical assays have confirmed that they inhibit SUMO conjugation. Mechanistic and biophysical analyses, along with molecular dynamics simulations, suggest that inhibition occurs via ligand-induced rigidification of Ubc9. These results provide novel insights into a previously unknown allosteric binding site that may be exploited to develop compounds with the potential to perturb a variety of protein-protein interactions that are critically dependent on Ubc9 activity.
Scientific Focus Area: Structural Biology
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