Get started
Work

Insights Into the Allosteric Inhibition of the SUMO E2 Enzyme Ubc9

Year: 2016
Type: article
Abstract: Conjugation of the small ubiquitin-like modifier (SUMO) to protein substrates is an important disease-associated posttranslational modification, although few inhibitors of this process are known. Herein, we report the discovery of an allosteric small-molecule binding site on Ubc9, the sole SUMO E2 enzyme. An X-ray crystallographic screen was used to identify two distinct small-molecule fragments that bind to Ubc9 at a site distal to its catalytic cysteine. These fragments and related compounds inhibit SUMO conjugation in biochemical assays with potencies of 1.9-5.8 mm. Mechanistic and biophysical analyses, coupled with molecular dynamics simulations, point toward ligand-induced rigidification of Ubc9 as a mechanism of inhibition.
DOI: 10.1002/anie.201511351
Authors: William M. Hewitt, George T. Lountos, Katherine Zlotkowski, Samuel D. Dahlhauser, Lindsey B. Saunders, Danielle Needle, Joseph E. Tropea, Chendi Zhan, Guanghong Wei, Buyong Ma, Ruth Nussinov, David S. Waugh, John S. Schneekloth
Institutions: Frederick National Laboratory for Cancer Research, National Cancer Institute, Center for Cancer Research, Leidos Biomedical Research Inc. (United States), Fudan University, State Key Laboratory of Surface Physics, Tel Aviv University
Language: English
Open Access status: green
Funders: Center for Cancer Research, U.S. Department of Energy, Frederick National Laboratory for Cancer Research, National Institutes of Health, Office of Science, National Cancer Institute, Basic Energy Sciences, Argonne National Laboratory
Awards: Identification of Inhibitors of Protein Sumoylation, G1756342139, G18202666, G2123841078, G3503792436, G386607036, G4988656331, G572720644, G5888954722, G6374948078
OpenAlex ID: W2313722115
FWCI: 0.903
Cites: 33
Cited by: 23
Related to: 10